Diazabicyclic substituted imidazopyrimidines and their use for the treatment of breathing disorders

ABSTRACT

The present invention relates to novel diazabicyclically substituted imidazo[1,2-a]pyrimidine derivatives, to methods for producing the same, to the use thereof either alone or in combinations for the treatment and/or prevention of diseases, as well as to their use for preparing medicaments for the treatment and/or prevention of diseases, especially for treatment and/or prevention of breathing disorders, including sleep-related breathing disorders such as obstructive and central sleep apnoea and snoring.

The present application relates to novel diazabicyclically substituted imidazo[1,2-a]pyrimidine derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of respiratory disorders including sleep-related respiratory disorders such as obstructive sleep apnoeas and central sleep apnoeas and snoring.

Potassium channels are virtually ubiquitous membrane proteins which are involved in a large number of different physiological processes. This also includes the regulation of the membrane potential and the electric excitability of neurons and muscle cells. Potassium channels are divided into three major groups which differ in the number of transmembrane domains (2, 4 or 6). The group of potassium channels where two pore-forming domains are flanked by four transmembrane domains is referred to as K2P channels. Functionally, the K2P channels mediate, substantially time- and voltage-independently, K⁺ background currents, and their contribution to the maintenance of the resting membrane potential is crucial. The family of the K2P channels includes 15 members which are divided into six subfamilies, based on similarities in sequence, structure and function: TWIK, TREK, TASK, TALK, THIK and TRESK.

Of particular interest are TASK-1 (KCNK3 or K2P3.1) and TASK-3 (KCNK9 or K2P9.1) of the TASK (TWIK-related acid-sensitive K⁺ channel) subfamily. Functionally, these channels are characterized in that, during maintenance of voltage-independent kinetics, they have “leak” or “background” currents flowing through them, and they respond to numerous physiological and pathological influences by increasing or decreasing their activity. Characteristic of TASK channels is the sensitive reaction to a change in extracellular pH: the channels are inhibited at acidic pH and activated at alkaline pH.

TASK-1 is expressed mainly in the central nervous system and in the cardiovascular system. Relevant expression of TASK-1 was demonstrated in the brain, in spinal ganglia, in motoneurons of the Nervus hypoglossus and Nervus trigeminus, in the heart, Glomus caroticum, the pulmonary artery, aorta, lung, pancreas, placenta, uterus, kidney, adrenal gland, small intestine and stomach, and also on T lymphocytes. TASK-3 is expressed mainly in the central nervous system. Relevant expression of TASK-3 was demonstrated in the brain, in motoneurons of the Nervus hypoglossus and Nervus trigeminus and in neuroepithelial cells of the Glomus caroticum and the lung, and also on T lymphocytes. A lower expression is found in the heart, stomach, testicular tissue and adrenal gland.

TASK-1 and TASK-3 channels play a role in respiratory regulation. Both channels are expressed in the respiratory neurons of the respiratory centre in the brain stem, inter alia in neurons which generate the respiratory rhythm (ventral respiratory group with pre-Bötzinger complex), and in the noradrenergic Locus caeruleus, and also in serotonergic neurons of the raphe nuclei. Owing to the pH dependency, here the TASK channels have the function of a sensor which translates changes in extracellular pH into corresponding cellular signals [Bayliss et al., Pflugers Arch. 467, 917-929 (2015)]. TASK-1 and TASK-3 are also expressed in the Glomus caroticum, a peripheral chemoreceptor which measures pH, O₂ and CO₂ content of the blood and transmits signals to the respiratory centre in the brain stem to regulate respiration. It was shown that TASK-1 knock-out mice have a reduced ventilatory response (increase of respiratory rate and tidal volume) to hypoxia and normoxic hypercapnia [Trapp et al., J. Neurosci. 28, 8844-8850 (2008)]. Furthermore, TASK-1 and TASK-3 channels were demonstrated in motoneurons of the Nervus hypoglossus, the XIIth cranial nerve, which has an important role in keeping the upper airways open [Berg et al., J. Neurosci. 24, 6693-6702 (2004)].

In a sleep apnoea model in the anaesthetized pig, intranasal administration of a potassium channel blocker which blocks the TASK-1 channel in the nanomolar range led to inhibition of collapsibility of the pharyngeal respiratory musculature and sensitization of the negative pressure reflex of the upper airways. It is assumed that intranasal administration of the potassium channel blocker depolarizes mechanoreceptors in the upper airways and, via activation of the negative pressure reflex, leads to increased activity of the musculature of the upper airways, thus stabilizing the upper airways and preventing collapse. By virtue of this stabilization of the upper airways, the TASK channel blockade may be of great importance for obstructive sleep apnoea and also for snoring [Wirth et al., Sleep 36, 699-708 (2013); Kiper et al., Pflugers Arch. 467, 1081-1090 (2015)].

Obstructive sleep apnoea (OSA) is a sleep-related respiratory disorder which is characterized by repeat episodes of obstruction of the upper airways. When breathing in, the patency of the upper airways is ensured by the interaction of two opposite forces. The dilative effects of the musculature of the upper airways counteract the negative intraluminal pressure, which constricts the lumen. The active contraction of the diaphragm and the other auxiliary respiratory muscles generates a negative pressure in the airways, thus constituting the driving force for breathing. The stability of the upper airways is substantially determined by the coordination and contraction property of the dilating muscles of the upper airways.

The Musculus genioglossus plays a decisive role in the pathogenesis of obstructive sleep apnoea. The activity of the Musculus genioglossus increases with decreasing pressure in the pharynx in the sense of a dilative compensation mechanism. Innervated by the Nervus hypoglossus, it drives the tongue forward and downward, thus widening the pharyngeal airway [Verse et al., Somnologie 3, 14-20 (1999)]. Tensioning of the dilating muscles of the upper airways is modulated inter alia via mechanoreceptors/stretch receptors in the nasal cavity/pharynx [Bouillette et al., J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 46, 772-779 (1979)]. In sleeping patients suffering from serious sleep apnoea, under local anaesthesia of the upper airway an additional reduction of the activity of the Musculus genioglossus can be observed [Berry et al., Am. J. Respir. Crit. Care Med. 156, 127-132 (1997)]. Patients suffering from obstructive sleep apnoea have high mortality and morbidity as a result of cardiovascular disorders such as hypertension, myocardial infarction and stroke [Vrints et al., Acta Clin. Belg. 68, 169-178 (2013)].

In the case of central sleep apnoea, owing to impaired brain function and impaired respiratory regulation there are episodic inhibitions of the respiratory drive. Central respiratory disorders result in mechanical respiratory arrests, i.e. during these episodes there is no breathing activity; temporarily, all respiratory muscles including the diaphragm are at rest. In the case of central sleep apnoea, there is no obstruction of the upper airways.

In the case of primary snoring, there is likewise no obstruction of the upper airways. However, owing to the constriction of the upper airways, the flow rate of the air that is inhaled and exhaled increases. This, combined with the relaxed musculature, causes the soft tissues of the oral cavity and the pharynx to flutter in the stream of air. This gentle vibration then generates the typical snoring noises.

Obstructive snoring (upper airway resistance syndrome, heavy snoring, hypopnoea syndrome) is caused by repeat partial obstruction of the upper airways during sleep. This results in an increased airway resistance and thus in an increase in work of breathing with considerable fluctuations in intrathoracic pressure. During inspiration, the negative intrathoracic pressure may reach values similar to those that are encountered as a result of complete airway obstruction during obstructive sleep apnoea. The pathophysiological consequences for heart, circulation and sleep quality correspond to those of obstructive sleep apnoea. As in obstructive sleep apnoea, the pathogenesis is assumed to be an impaired reflex mechanism of the pharynx-dilating muscles during inspiration when sleeping. Frequently, obstructive snoring is the preliminary stage of obstructive sleep apnoea [Hollandt et al., HNO 48, 628-634 (2000)].

In addition, TASK channels also appear to play a role in the apoptosis of neurons. In the animal model of myelin oligodendrocyte glycoprotein (MOG)-induced autoimmune encephalomyelitis, an animal model of multiple sclerosis, TASK-1 knock-out mice showed reduced neuronal degeneration. By preventing neuronal apoptosis, inhibition of TASK channels appears to act neuroprotectively, and may thus be of interest for the treatment of neurodegenerative disorders [Bittner et al., Brain 132, 2501-2516 (2009)].

Furthermore, it has been described that T lymphocytes express TASK-1 and TASK-3 channels and that inhibition of these channels leads to reduced cytokine production and proliferation after stimulation of T lymphocytes. The selective inhibition of TASK channels on T lymphocytes improved the course of the disease in an animal model of multiple sclerosis. The blockade of TASK channels may therefore also be of importance for treatment of autoimmune disorders [Meuth et al., J. Biol. Chem. 283, 14559-14579 (2008)].

TASK-1 and TASK-3 are also expressed in the heart [Rinne et al., J. Mol. Cell. Cardiol. 81, 71-80 (2015)]. Since TASK-1 is expressed particularly strongly in the nervous stimuli conduction system and in the atrium, this channel may have a role in disrupting stimuli conduction or triggering supraventricular arrhythmias. In the heart, TASK-1 appears to contribute to a background current which for its part contributes to maintenance of the resting potential, to action potential duration and to repolarization [Kim et al., Am. J. Physiol. 277, H1669-1678 (1999)]. Using human heart muscle cells, it was shown that blockade of the TASK-1 ion current results in a longer action potential [Limberg et al., Cell. Physiol. Biochem. 28, 613-624 (2011)]. Furthermore, for TASK-1 knock-out mice a prolonged QT time was demonstrated [Decher et al., Cell. Physiol. Biochem. 28, 77-86 (2011)]. Inhibition of TASK channels may therefore be of importance for the treatment of cardiac arrhythmias, in particular atrial fibrillation.

In certain vessels, TASK channels also appear to play a role in the regulation of the vascular tone. A relevant expression of TASK-1 was noticed in smooth muscles of pulmonary and mesenteric arteries. In studies on smooth muscle cells of human pulmonary arteries, it was shown that TASK-1 plays a role in the regulation of the pulmonary vascular tone. TASK-1 may be involved in hypoxic and acidosis-induced pulmonary vasoconstriction [Tang et al., Am. J. Respir. Cell. Mol. Biol. 41, 476-483 (2009)].

In glomerulosa cells of the adrenal cortex, TASK-1 plays a role in potassium conductivity [Czirjak et al., Mol. Endocrinol. 14, 863-874 (2000)].

Possibly, TASK channels also play an important role in apoptosis and tumorigenesis. In breast cancer, colon cancer and lung cancer biopsies and also in metastasizing prostate cancer and in melanoma cells, TASK-3 has been found to be strongly overexpressed [Mu et al., Cancer Cell 3, 297-302 (2003); Kim et al., APMIS 112, 588-594 (2004); Pocsai et al., Cell. Mol. Life Sci. 63, 2364-2376 (2006)]. A point mutation at the TASK-3 channel, which switches off the channel function, simultaneously cancels the tumour-forming action (proliferation, tumour growth, apoptosis resistance) [Mu et al., Cancer Cell 3, 297-302 (2003)]. Overexpression of TASK-3 and TASK-1 in a murine fibroblast cell line (C8 cells) inhibits intracellular apoptosis routes [Liu et al., Brain Res. 1031, 164-173 (2005)]. Accordingly, the blockade of TASK channels may also be relevant for the treatment of various neoplastic disorders.

Therefore, it is an object of the present invention to provide novel substances which act as potent and selective blockers of TASK-1 and TASK-3 channels and, as such, are suitable in particular for the treatment and/or prevention of respiratory disorders including sleep-related respiratory disorders such as obstructive and central sleep apnoeas and snoring, and also other disorders.

US 2002/0022624-A1 describes various azaindole derivatives including imidazo[1,2-a]pyridines as substance P antagonists for the treatment of CNS disorders. WO 02/02557-A2 and WO 2009/143156-A2 disclose 2-phenylimidazo[1,2-a]pyridine derivatives which, as modulators of GABA_(A) receptors, are likewise suitable for treating CNS disorders. WO 2011/113606-A1 and WO 2012/143796-A2 disclose bicyclic imidazole derivatives suitable for the treatment of bacterial infections and inflammatory disorders. EP 2671582-A1 discloses further bicyclic imidazole derivatives and options for their therapeutic use as inhibitors of T type calcium channels. WO 2012/130322-A1 describes 2,6-diaryl-3-(piperazinomethyl)imidazo[1,2-a]pyridine derivatives which, by virtue of their HIF-1 inhibiting activity, are suitable in particular for the treatment of inflammatory and hyperproliferative disorders. WO 2014/187922-A1 discloses various 2-phenyl-3-(heterocyclomethyl)imidazo[1,2-a]pyridine and -imidazo[1,2-a]pyrazine derivatives which can be employed as inhibitors of glucose transporters (GLUT) for treating inflammatory, proliferative, metabolic, neurological and/or autoimmune disorders. WO 2015/144605-A1 and WO 2017/050732-A1, inter alia, describe acylated bicyclic amine compounds suitable as inhibitors of autotaxin and of lysophosphatidic acid production for the treatment of various disorders. WO 2016/084866-A1, WO 2016/085783-A1 and WO 2016/088813-A1 disclose acylated diazabicyclic compounds which, by virtue of their antagonistic action on orexin receptors, can be used for treating neurodegenerative, neurological and psychiatric disorders, mental disorders and eating and sleep disorders, in particular sleeplessness.

Furthermore, the compound ethyl 4-[(2-phenylimidazo[1,2-a]pyrimidin-3-yl)methyl]piperazin-1-carboxylate [CAS Registry No. 1783141-19-4] has been indexed by Chemical Abstracts as “Chemical Library” substance without literature reference; a medicinal-therapeutic application of this compound has hitherto not been described.

The present invention provides compounds of the general formula (I)

in which

the ring Q represents a diazaheterobicyclic system of the formula

-   -   in which * denotes the bond to the adjacent CHR² group and **         the bond to the carbonyl group,

-   A represents CH or N,

-   R¹ represents halogen, cyano, cyclopropyl or cyclobutyl     -   where (C₁-C₄)-alkyl may be up to trisubstituted by fluorine and         cyclopropyl and cyclobutyl may be up to disubstituted by         fluorine,

-   R² represents hydrogen or methyl,

and

-   R³ represents (C₄-C₆)-cycloalkyl in which a ring CH₂ group may be     replaced by —O—,

or

-   R³ represents a phenyl group of the formula (a), a pyridyl group of     the formula (b) or (c) or an azole group of the formula (d), (e) or     (f)

-   -   in which *** marks the bond to the adjacent carbonyl group and     -   R⁴ represents hydrogen, fluorine, chlorine, bromine or methyl,     -   R⁵ represents hydrogen, fluorine, chlorine, bromine, cyano,         (C₁-C₃)-alkyl or (C₁-C₃)-alkoxy,         -   where (C₁-C₃)-alkyl and (C₁-C₃)-alkoxy may each be up to             trisubstituted by fluorine,     -   R⁶ represents hydrogen, fluorine, chlorine, bromine or methyl,     -   R⁷ represents hydrogen, (C₁-C₃)-alkoxy, cyclobutyloxy,         oxetan-3-yloxy, tetrahydrofuran-3-yloxy,         tetrahydro-2H-pyran-4-yloxy, mono-(C₁-C₃)-alkylamino,         di-(C₁-C₃)-alkylamino or (C₁-C₃)-alkylsulfanyl,         -   where (C₁-C₃)-alkoxy may be up to trisubstituted by             fluorine,     -   R⁸ represents hydrogen, fluorine, chlorine, bromine,         (C₁-C₃)-alkyl or (C₁-C₃)-alkoxy,     -   R^(9A) and R^(9B) are identical or different and independently         of one another represent hydrogen, fluorine, chlorine, bromine,         (C₁-C₃)-alkyl, cyclopropyl or (C₁-C₃)-alkoxy         -   where (C₁-C₃)-alkyl and (C₁-C₃)-alkoxy may each be up to             trisubstituted by fluorine,     -   and     -   Y represents O or S,

or

-   R³ represents an —OR¹⁰ or —NR¹¹R¹² group in which     -   R¹⁰ represents (C₁-C₆)-alkyl, (C₄-C₆)-cycloalkyl or         [(C₃-C₆)-cycloalkyl]methyl,     -   R¹¹ represents hydrogen or (C₁-C₃)-alkyl     -   and     -   R¹² represents (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, phenyl or         benzyl,         -   where (C₁-C₆)-alkyl may be up to trisubstituted by fluorine,         -   and         -   where phenyl and the phenyl group in benzyl may be up to             trisubstituted by identical or different radicals selected             from the group consisting of fluorine, chlorine, methyl,             ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy             and (trifluoromethyl)sulfanyl,     -   or     -   R¹¹ and R¹² are attached to one another and, together with the         nitrogen atom to which they are bonded, form a pyrrolidine,         piperidine, morpholine or thiomorpholine ring,

and the salts, solvates and solvates of the salts thereof.

Inventive compounds are the compounds of the formula (I) and the salts, solvates and solvates of the salts thereof, the compounds of the formulae (I-A), (I-B), (I-C), (I-D) and (I-E) cited hereinafter that are encompassed by formula (I) and the salts, solvates and solvates of the salts thereof, and the compounds cited hereinafter as working examples that are encompassed by formula (I) and the salts, solvates and solvates of the salts thereof, if the compounds cited hereinafter that are encompassed by formula (I) are not already salts, solvates and solvates of the salts.

Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also encompassed are salts which are not themselves suitable for pharmaceutical applications but can be used, for example, for the isolation, purification or storage of the compounds of the invention.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenedisulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, benzoic acid and embonic acid.

Solvates in the context of the invention are described as those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of the solvates in which the coordination is with water. Solvates preferred in the context of the present invention are hydrates.

The compounds according to the invention may, depending on their structure, exist in different stereoisomeric forms, i.e. in the form of configurational isomers or else, if appropriate, as conformational isomers (enantiomers and/or diastereomers, including those in the case of atropisomers). The present invention therefore encompasses the enantiomers and diastereomers, and the respective mixtures thereof. The stereoisomerically homogeneous constituents can be isolated from such mixtures of enantiomers and/or diastereomers in a known manner; chromatography processes are preferably employed for the purpose, especially HPLC chromatography on chiral or achiral separation phases. In the case of chiral amines as intermediates or end products, separation is alternatively also possible via diastereomeric salts using enantiomerically pure carboxylic acids.

If the compounds of the invention can occur in tautomeric forms, the present invention encompasses all the tautomeric forms.

The present invention also encompasses all suitable isotopic variants of the compounds according to the invention. An isotopic variant of a compound according to the invention is understood here to mean a compound in which at least one atom within the compound according to the invention has been exchanged for another atom of the same atomic number, but with a different atomic mass from the atomic mass which usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound according to the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I. Particular isotopic variants of a compound according to the invention, especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active ingredient distribution in the body; due to the comparatively easy preparability and detectability, especially compounds labelled with ³H or ¹⁴C isotopes are suitable for this purpose. In addition, the incorporation of isotopes, for example of deuterium, can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required; such modifications of the compounds of the invention may therefore possibly also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds of the invention can be prepared by commonly used processes known to those skilled in the art, for example by the methods described further down and the procedures described in the working examples, by using corresponding isotopic modifications of the respective reagents and/or starting compounds.

The present invention additionally also encompasses prodrugs of the compounds according to the invention. The term “prodrugs” refers here to compounds which may themselves be biologically active or inactive, but are converted while present in the body, for example by a metabolic or hydrolytic route, to compounds of the invention.

In the context of the present invention, unless specified otherwise, the substituents and radicals are defined as follows:

In the context of the invention, (C₁-C₆)-alkyl is a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl.

In the context of the invention, (C₁-C₄)-alkyl is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

In the context of the invention, (C₁-C₃)-alkyl is a straight-chain or branched alkyl radical having 1 to 3 carbon atoms. Examples include: methyl, ethyl, n-propyl and isopropyl.

(C₁-C₃)-Alkoxy in the context of the invention is a straight-chain or branched alkoxy radical having 1 to 3 carbon atoms. Examples include: methoxy, ethoxy, n-propoxy and isopropoxy.

Mono-(C₁-C₃)-alkylamino in the context of the invention is an amino group having a straight-chain or branched alkyl substituent having 1 to 3 carbon atoms. Examples include: methylamino, ethylamino, n-propylamino and isopropylamino.

Di-(C₁-C₃)-alkylamino in the context of the invention is an amino group having two identical or different straight-chain or branched alkyl substituents each having 1 to 3 carbon atoms. Examples include: N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-methylamino, N,N-di-n-propylamino, N-isopropyl-N-n-propylamino and N,N-diisopropylamino.

(C₁-C₃)-Alkylsulfanyl [also referred to as (C₁-C₃)-alkylthio] in the context of the invention is a straight-chain or branched alkyl radical having 1 to 3 carbon atoms which is attached to the remainder of the molecule via a sulfur atom. Examples include: methylsulfanyl, ethylsulfanyl, n-propylsulfanyl and isopropylsulfanyl.

(C₃-C₆)-Cycloalkyl in the context of the invention is a monocyclic saturated cycloalkyl group having 3 to 6 ring carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

(C₄-C₆)-Cycloalkyl in the context of the invention is a monocyclic saturated cycloalkyl group having 4 to 6 carbon atoms. Examples include: cyclobutyl, cyclopentyl and cyclohexyl.

Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to fluorine, chlorine or bromine.

In the context of the present invention, all radicals which occur more than once are defined independently of one another. When radicals in the compounds of the invention are substituted, the radicals may be mono- or polysubstituted, unless specified otherwise. Substitution by one substituent or by two identical or different substituents is preferred. Particular preference is given to substitution by one substituent.

Preference is given in the context of the present invention to compounds of the formula (I) in which the ring Q represents a diazaheterobicyclic system of the formula

-   -   in which * denotes the bond to the adjacent CHR² group and **         the bond to the carbonyl group,

-   A represents CH,

-   R¹ represents fluorine, chlorine, bromine, methyl, isopropyl,     tert-butyl, cyclopropyl or cyclobutyl,

-   R² represents hydrogen,

and

-   R³ represents cyclobutyl, cyclopentyl or cyclohexyl

or

-   R³ represents a phenyl group of the formula (a), a pyridyl group of     the formula (b) or an azole group of the formula (d), (e) or (f)

-   -   in which *** marks the bond to the adjacent carbonyl group and     -   R⁴ represents hydrogen, fluorine or chlorine,     -   R⁵ represents fluorine, chlorine, cyano, (C₁-C₃)-alkyl,         (C₁-C₃)-alkoxy or trifluoromethoxy,     -   R⁶ represents hydrogen, fluorine, chlorine, bromine or methyl,     -   R⁷ represents (C₁-C₃)-alkoxy, cyclobutyloxy or         (C₁-C₃)-alkylsulfanyl,         -   where (C₁-C₃)-alkoxy may be up to trisubstituted by             fluorine,     -   R^(9A) and R^(9B) are identical or different and independently         of one another represent hydrogen, chlorine, bromine,         (C₁-C₃)-alkyl or cyclopropyl,         -   where (C₁-C₃)-alkyl may be up to trisubstituted by fluorine,     -   and     -   Y represents O or S,

and the salts, solvates and solvates of the salts thereof.

A particular embodiment of the present invention relates to compounds of the formula (I) in which the ring Q represents a diazaheterobicyclic system of the formula

-   -   in which * denotes the bond to the adjacent CHR² group and **         the bond to the carbonyl group,

and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention relates to compounds of the formula (I) in which

the ring Q represents a diazaheterobicyclic system of the formula

-   -   in which * denotes the bond to the adjacent CHR² group and **         the bond to the carbonyl group,

and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention relates to compounds of the formula (I) in which

the ring Q represents a diazaheterobicyclic system of the formula

-   -   in which * denotes the bond to the adjacent CHR² group and **         the bond to the carbonyl group,

and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention relates to compounds of the formula (I) in which

A represents CH,

and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention relates to compounds of the formula (I) in which

R¹ represents chlorine, bromine, isopropyl or cyclopropyl,

and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention relates to compounds of the formula (I) in which

R² represents hydrogen,

and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention relates to compounds of the formula (I) in which

R³ represents cyclopentyl or cyclohexyl,

and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention relates to compounds of the formula (I) in which

R³ represents a phenyl group of the formula (a)

-   -   in which *** marks the bond to the adjacent carbonyl group,     -   R⁴ represents hydrogen, fluorine or chlorine     -   and     -   R⁵ represents fluorine, chlorine, (C₁-C₃)-alkyl or         (C₁-C₃)-alkoxy,

and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention relates to compounds of the formula (I) in which

R³ represents a pyridyl group of the formula (b)

-   -   in which *** marks the bond to the adjacent carbonyl group,     -   R⁶ represents hydrogen, fluorine, chlorine, bromine or methyl     -   and     -   R⁷ represents (C₁-C₃)-alkoxy, cyclobutyloxy or         (C₁-C₃)-alkylsulfanyl,         -   where (C₁-C₃)-alkoxy may be up to trisubstituted by             fluorine,

and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention relates to compounds of the formula (I) in which

R³ represents an azole group of the formula (d), (e) or (f)

-   -   in which *** marks the bond to the adjacent carbonyl group,     -   R^(9A) and R^(9B) are identical or different and independently         of one another represent hydrogen, chlorine, bromine,         (C₁-C₃)-alkyl or cyclopropyl,         -   where (C₁-C₃)-alkyl may be up to trisubstituted by fluorine,     -   and     -   Y represents O or S,

and the salts, solvates and solvates of the salts thereof.

In the context of the present invention, particular preference is given to compounds of the formula (I) in which

the ring Q represents a diazaheterobicyclic system of the formula

-   -   in which * denotes the bond to the adjacent CHR² group and **         the bond to the carbonyl group,

-   A represents CH,

-   R¹ represents chlorine, bromine, isopropyl or cyclopropyl,

-   R² represents hydrogen,

and

-   R³ represents cyclopentyl or cyclohexyl,

or

-   R³ represents a phenyl group of the formula (a), a pyridyl group of     the formula (b) or an azole group of the formula (d), (e) or (f)

-   -   in which *** marks the bond to the adjacent carbonyl group and     -   R⁴ represents hydrogen, fluorine or chlorine,     -   R⁵ represents fluorine, chlorine, methyl, isopropyl, methoxy or         ethoxy,     -   R⁶ represents hydrogen, fluorine, chlorine, bromine or methyl,     -   R⁷ represents methoxy, difluoromethoxy, trifluoromethoxy,         isopropoxy, cyclobutyloxy or methylsulfanyl,     -   R^(9A) and R^(9B) are identical or different and independently         of one another represent hydrogen, methyl, trifluoromethyl,         ethyl, isopropyl or cyclopropyl,     -   and     -   Y represents O or S,

and the salts, solvates and solvates of the salts thereof.

The individual radical definitions specified in the respective combinations or preferred combinations of radicals are, independently of the respective combinations of the radicals specified, also replaced as desired by radical definitions of other combinations. Particular preference is given to combinations of two or more of the abovementioned preferred ranges.

The invention furthermore provides a process for preparing compounds of the formula (I) according to the invention in which the radical R² represents hydrogen, characterized in that a compound of the formula (II)

in which A and R¹ have the meanings given above

is reacted in the presence of a suitable reducing agent either

[A] with a compound of the formula (III)

-   -   in which R³ and the ring Q have the meanings given above     -   to give a compound of the formula (I-A)

-   -   in which A, R¹, R³ and the ring Q have the meanings given above

or

[B] with a protected diazaheterobicyclic system of the formula (IV)

in which the ring Q has the meaning given above

and

-   PG represents a suitable amino protecting group, for example     tert-butoxycarbonyl, benzyloxycarbonyl or     (9H-fluoren-9-ylmethoxy)carbonyl

at first to give a compound of the formula (V)

in which A, PG, R¹ and the ring Q have the meanings given above,

then the protecting group PG is cleaved and the resulting compound of the formula (VI)

in which A, R¹ and the ring Q have the meanings given above

is then reacted, depending on the specific definition of the R³ radical,

[B-1] with a carboxylic acid of the formula (VII)

-   -   in which     -   R^(3A) represents (C₄-C₆)-cycloalkyl in which a ring CH₂ group         may be replaced by —O—, or is a phenyl group of the formula (a),         a pyridyl group of the formula (b) or (c) or an azole group of         the formula (d), (e) or (f), as described above,     -   with activation of the carboxylic acid function in (VII), or is         reacted with the corresponding acid chloride of the formula         (VIII)

-   -   in which R^(3A) has the meaning given above     -   to give a compound of the formula (I-B)

-   -   in which A, R¹, R^(3A) and the ring Q have the meanings given         above

or

[B-2] with a chloroformate or carbamoyl chloride of the formula (IX)

in which

R^(3B) represents the —OR¹⁰ or —NR^(11A)R¹² group in which

-   -   R¹⁰ and R¹² have the meanings given above     -   and     -   R^(11A) has the definition of R¹¹ given above, but is not         hydrogen,

to give a compound of the formula (I-C)

-   -   in which A, R¹, R^(3B) and the ring Q have the meanings given         above

or

[B-3] with an isocyanate of the formula (X)

R¹²—N═C═O  (X)

-   -   in which R¹² has the meaning given above     -   to give a compound of the formula (I-D)

-   -   in which A, R¹, R¹² and the ring Q have the meanings given above

and the compounds of the formulae (I-A), (I-B), (I-C) and (I-D) thus obtained are optionally separated into their enantiomers and/or diastereomers and/or optionally converted with the appropriate (i) solvents and/or (ii) acids to the solvates, salts and/or solvates of the salts thereof.

Suitable reducing agents for the process steps [A] (II)+(III)→(I-A) and [B] (II)+(IV)→(V) [reductive aminations] for such purposes are customary alkali metal borohydrides such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride; preference is given to using sodium triacetoxyborohydride. The addition of an acid, such as acetic acid in particular, and/or of a dehydrating agent, for example molecular sieve or trimethyl orthoformate or triethyl orthoformate, may be advantageous in these reactions.

Suitable solvents for these reactions are especially alcohols such as methanol, ethanol, n-propanol or isopropanol, ethers such as diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, polar aprotic solvents such as acetonitrile or N,N-dimethylformamide (DMF) or mixtures of such solvents; preference is given to using tetrahydrofuran. The reactions are generally effected within a temperature range of 0° C. to +50° C.

The protecting group PG used in compound (IV) may be a standard amino protecting group, for example tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Z) or (9H-fluoren-9-ylmethoxy)carbonyl (Fmoc); preference is given to using tert-butoxycarbonyl (Boc). The detachment of the protecting group in method step [B] (V)→(VI) is effected by known methods. Thus, the tert-butoxycarbonyl group is typically cleaved by treatment with a strong acid such as hydrogen chloride, hydrogen bromide or trifluoroacetic acid, in an inert solvent such as diethyl ether, 1,4-dioxane, dichloromethane or acetic acid. In the case of benzyloxycarbonyl as protecting group, this is preferably removed by hydrogenolysis in the presence of a suitable palladium catalyst such as palladium on activated carbon. The (9H-fluoren-9-ylmethoxy)carbonyl group is generally cleaved with the aid of a secondary amine base such as diethylamine or piperidine [see e.g. T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999; P. J. Kocienski, Protecting Groups, 3^(rd) edition, Thieme, 2005].

Certain compounds of the formula (V), especially those in which PG is tert-butoxycarbonyl, likewise have significant inhibitory activity with respect to TASK-1 and/or TASK-3, and in this respect are also encompassed by the scope of definition of the present invention, i.e. the compounds of the formula (I).

The process step [B-1] (VI)+(VII)→(I-B) [amide formation] is conducted by known methods with the aid of a condensing or activating agent. Suitable agents of this kind are, for example, carbodiimides such as N,N′-diethyl-, N,N′-dipropyl-, N,N′-diisopropyl-, N,N′-dicyclohexylcarbodiimide (DCC) or N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as N,N′-carbonyldiimidazole (CDI) or isobutyl chloroformate, 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, α-chlorenamines such as 1-chloro-N,N,2-trimethylprop-1-en-1-amine, 1,3,5-triazine derivatives such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, phosphorus compounds such as n-propanephosphonic anhydride (PPA), diethyl cyanophosphonate, diphenylphosphoryl azide (DPPA), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), or uronium compounds such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) or 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), optionally in combination with further auxiliaries such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and also as base an alkali metal carbonate, for example sodium carbonate or potassium carbonate, or a tertiary amine base such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine (NMM), N-methylpiperidine (NMP), pyridine or 4-N,N-dimethylaminopyridine (DMAP). The condensing agent or activating agent used with preference is O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) in combination with N,N-diisopropylethylamine as base.

The alternative process via the carbonyl chloride (VIII)[(VI)+(VIII)→(I-B)] is generally effected in the presence of a base such as sodium carbonate, potassium carbonate, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine (NMM), N-methylpiperidine (NMP), pyridine, 2,6-dimethylpyridine, 4-N,N-dimethylaminopyridine (DMAP), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); preference is given to using triethylamine or N,N-diisopropylethyl amine.

Suitable inert solvents for these amide-forming reactions are, for example, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis(2-methoxyethyl) ether, hydrocarbons such as benzene, toluene, xylene, pentane, hexane or cyclohexane, halohydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or polar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, butyronitrile, pyridine, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N′-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP); it is also possible to use mixtures of such solvents. Preference is given to using dichloromethane, 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide or mixtures of these solvents. The reactions are generally conducted within a temperature range of from −20° C. to +60° C., preferably at from 0° C. to +40° C.

The process [B-2] (VI)+(IX)→(I-C) [formation of urethanes or substituted ureas] is conducted under similar reaction conditions with regard to solvent, addition of base and temperature as described above for the amide formation [B-1] (VI)+(VIII)→(I-B).

The reaction [B-3] (VI)+(X)→(I-D) is likewise effected in one of the above-listed inert solvents or solvent mixtures at a temperature in the range from 0° C. to +60° C.; the addition of a base in this reaction can optionally be dispensed with.

The amine compound (VI) can also be used in the process steps [B-1] (VI)+(VII) or (VIII)→(I-B), [B-2] (VI)+(IX)→(I-C) and [B-3] (VI)+(X)→(I-D) in the form of a salt, for example as hydrochloride or trifluoroacetate. In such a case, the conversion is effected in the presence of an appropriately increased amount of the respective auxiliary base used.

Compounds of the formula (I) according to the invention in which the radical R² represents methyl can be obtained by reacting the carbaldehyde of the formula (II) already mentioned above

in which A and R¹ have the meanings given above

initially with methylmagnesium bromide to give the secondary alcohol of the formula (XI)

in which A and R¹ have the meanings given above,

then converting this with the aid of triphenylphosphine and carbon tetrabromide into the corresponding bromide of the formula (XII)

in which A and R¹ have the meanings given above,

subsequently reacting with a protected diazaheterobicyclic system of the formula (IV)

in which the ring Q has the meaning given above

and

PG represents a suitable amino protecting group, for example tert-butoxycarbonyl, benzyloxycarbonyl or (9H-fluoren-9-ylmethoxy)carbonyl

to give a compound of the formula (XIII)

in which A, PG, R¹ and the ring Q have the meanings given above,

thereafter claeving the protecting group PG and then converting the resulting compound of the formula (XIV)

in which A, R¹ and the ring Q have the meanings given above

depending on the specific meaning of the radical R³ according to one of the processes [B-1], [B-2] and [B-3] described above into the target compound of the formula (I-E)

in which A, R¹, R³ and the ring Q have the meanings given above

and optionally separating the latter into their enantiomers and/or diastereomers and/or optionally reacting them with the corresponding (i) solvents and/or (ii) acids to give solvates, salts and/or solvates of the salts thereof.

The conversion of the carbaldehyde (II) with methylmagnesium bromide into the secondary alcohol (XI) is typically carried out in an ethereal solvent such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran or a mixture thereof in a temperature range from −20° C. to +40° C. The subsequent conversion into the bromide (XII) is advantageously carried out under mild conditions using the reagent combination of triphenylphosphine and carbon tetrabromide in the presence of triethylamine as base (“Appel reaction”). The reaction is preferably carried out in dichloromethane as inert solvent in a temperature range from −10° C. to +30° C. For the subsequent reaction with the diazaheterobicyclic system (IV), the bromide (XII) is preferably not isolated beforehand but employed directly as crude product in a one-pot process with change of solvent. For this reaction (XII)+(IV)→(XIII), the solvent used is preferably acetonitrile, and the reaction generally takes place in a temperature range from +20° C. to +60° C.

The process steps (XIII)→(XIV) and (XIV)→(I-E) finally are carried out analogously to those described above for the processes [B] (V)→(VI) and [B-1], [B-2] or [B-3].

The processes described above can be conducted at atmospheric, elevated or reduced pressure (for example in the range from 0.5 to 5 bar); in general, the reactions are each carried out at atmospheric pressure.

Separation of the compounds of the invention into the corresponding enantiomers and/or

diastereomers can, as appropriate, optionally also be carried out at the early stage of the compounds (III), (IV), (V) or (VI) and (XI), (XIII) or (XIV), respectively, converted further in separated form in accordance with the process steps described above. Such a separation of stereoisomers can be conducted by customary methods known to the person skilled in the art. In the context of the present invention, preference is given to using chromatographic methods on chiral or achiral separation phases; in the case of chiral amines as intermediates or end products, separation can alternatively be effected via diastereomeric salts with the aid of enantiomerically pure carboxylic acids.

For their part, the compounds of the formula (II) can be prepared by processes known from the literature by condensing 2-aminopyrimidine (XV)

under the influence of a base with a compound of the formula (XVI)

in which A and R¹ have the meanings given above

and

X represents a suitable leaving group, for example chlorine, bromine or iodine to give an imidazo[1,2-a]pyrimidine derivative of the formula (XVII)

in which A and R¹ have the definitions given above

and then formylating this with a mixture of N,N-dimethylformamide and phosphorus oxychloride to give (II).

The condensation reaction (XV)+(XVI)→(XVII) is typically conducted in an alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol or n-butanol, in an ether such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis(2-methoxyethyl) ether, in a dipolar aprotic solvent such as N,N-dimethylformamide (DMF), N,N′-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP), or else in water, at a temperature in the range from +50° C. to +150° C.; the solvent used is preferably ethanol or water.

Bases suitable for this reaction are in particular alkali metal bicarbonates or carbonates such as sodium bicarbonate or potassium bicarbonate or lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate, alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, or else alumina; preference is given to using sodium bicarbonate or sodium hydroxide.

Optionally—if the reaction temperature is increased appropriately—the reaction can also be carried out without addition of a base.

The regioselective formylation (XVII)→(II) is carried out under the standard conditions of a Vilsmaier-Haack reaction by treatment of (XVII) with a preformed mixture of N,N-dimethylformamide and phosphorus oxychloride which is used in a large excess and simultaneously also serves as solvent. The reaction is generally carried out within a temperature range of from 0° C. to +100° C.

The compounds of the formulae (III), (IV), (VII), (VIII), (IX), (X), (XV) and (XVI) are either commercially available or described as such in the literature, or they can be prepared in a simple manner from other commercially available compounds by methods familiar to the person skilled in the art and known from the literature. Numerous detailed procedures and further literature references can also be found in the experimental section, in the section on the preparation of the starting compounds and intermediates.

The preparation of the compounds of the invention can be illustrated by way of example by the following reaction schemes:

The compounds of the invention have valuable pharmacological properties and can be used for prevention and treatment of diseases in humans and animals.

The compounds of the invention are potent and selective blockers of TASK-1 and TASK-3 channels and are therefore suitable for the treatment and/or prevention of disorders and pathological processes, in particular those caused by activation of TASK-1 and/or TASK-3 or by activated TASK-1 and/or TASK-3, and of disorders secondary to damage caused by TASK-1 and/or TASK-3.

For the purposes of the present invention, this includes in particular disorders from the group of the respiratory disorders and sleep-related respiratory disorders, such as obstructive sleep apnoea (in adults and children), primary snoring, obstructive snoring (upper airway resistance syndrome, heavy snoring, hypopnoea syndrome), central sleep apnoea, mixed sleep apnoeas, Cheyne-Stokes respiration, primary sleep apnoea of infancy, apparent life-threatening event, central sleep apnoea as a result of the use of medicaments or the use of other substances, obesity hypoventilation syndrome, disrupted central respiratory drive, sudden infant death, primary alveolar hypoventilation syndrome, postoperative hypoxia and apnoea, muscular respiratory disorders, respiratory disorders following long-term ventilation, respiratory disorders during adaptation in high mountains, acute and chronic pulmonary diseases with hypoxia and hypercapnia, sleep-related non-obstructive alveolar hypoventilation and the congenital central alveolar hypoventilation syndrome.

The compounds of the invention can additionally be used for treatment and/or prevention of neurodegenerative disorders such as dementia, dementia with Lewy bodies, Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease, Wilson's disease, progressive supranuclear paresis, corticobasal degeneration, tauopathy, frontotemporal dementia and parkinsonism linked to chromosome 17, multisystem atrophy, spinocerebellar ataxias, spinobulbar muscular atrophy of the Kennedy type, Friedreich's ataxia, dentatorubral-pallidoluysian atrophy, amyotrophic lateral sclerosis, primary lateral sclerosis, spinal muscular atrophy, Creutzfeldt-Jakob disease and variants of Creutzfeldt-Jakob disease, infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation, frontotemporal lobar degeneration with ubiquitin proteasome system and familial encephalopathy with neuroserpin inclusions.

In addition, the compounds of the invention can be used for treatment and/or prevention of neuroinflammatory and neuroimmunological disorders of the central nervous system (CNS), for example multiple sclerosis (Encephalomyelitis disseminata), transverse myelitis, Neuromyelitis optica, acute disseminated encephalomyelitis, optic neuritis, meningitis, encephalitis, demyelinating diseases and also inflammatory vascular changes in the central nervous system.

Moreover, the compounds of the invention are suitable for the treatment and/or prevention of neoplastic disorders such as, for example, skin cancer, breast cancer, lung cancer, colon cancer and prostate cancer.

The compounds of the invention are also suitable for treatment and/or prevention of cardiac arrhythmias, for example atrial and ventricular arrhythmias, conduction defects such as first- to third-degree atrio-ventricular blocks, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes and AV nodal re-entrant tachycardia.

Further cardiovascular disorders where the compounds of the invention can be employed for treatment and/or prevention are, for example, heart failure, coronary heart disease, stable and unstable angina pectoris, high blood pressure (hypertension), pulmonary-arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), renal hypertension, peripheral and cardial vascular disorders, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune cardiac disorders (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies), boxer cardiomyopathy, aneurysms, shock such as cardiogenic shock, septic shock and anaphylactic shock, furthermore thromboembolic disorders and ischaemias such as myocardial ischaemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischaemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, oedema formation such as, for example, pulmonary oedema, cerebral oedema, renal oedema or oedema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), and also to prevent restenoses, for example after thrombolysis therapies, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA), heart transplants and bypass operations.

In the context of the present invention, the term “heart failure” encompasses both acute and chronic forms of heart failure, and also specific or related disease types thereof, such as acute decompensated heart failure, right heart failure, left heart failure, global failure, ischaemic cardiomyopathy, dilatative cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, heart valve defects, heart failure associated with heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid valve stenosis, tricuspid valve insufficiency, pulmonary valve stenosis, pulmonary valve insufficiency, combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders and diastolic and systolic heart failure.

The compounds of the invention can additionally be used for treatment and/or prevention of asthmatic disorders of varying severity with intermittent or persistent characteristics (refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust-induced asthma), of various forms of bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), of bronchiectasis, pneumonia, farmer's lung and related disorders, coughs and colds (chronic inflammatory cough, iatrogenic cough), inflammation of the nasal mucosa (including medicament-related rhinitis, vasomotoric rhinitis and seasonal allergic rhinitis, for example hay fever) and of polyps.

The compounds of the invention are also suitable for treatment and/or prevention of renal disorders, in particular renal insufficiency and kidney failure. In the context of the present invention, the terms “renal insufficiency” and “kidney failure” encompass both acute and chronic manifestations thereof and also underlying or related renal disorders such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney disorders such as kidney transplant rejection and immunocomplex-induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome which can be characterized diagnostically, for example by abnormally reduced creatinine and/or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium and/or creatinine, altered activity of renal enzymes, for example glutamyl synthetase, altered urine osmolarity or urine volume, elevated microalbuminuria, macroalbuminuria, lesions on glomerulae and arterioles, tubular dilatation, hyperphosphatemia and/or need for dialysis. The present invention also encompasses the use of the compounds of the invention for treatment and/or prevention of sequelae of renal insufficiency, for example hypertension, pulmonary oedema, heart failure, uraemia, anaemia, electrolyte disturbances (for example hyperkalaemia, hyponatraemia) and disturbances in bone and carbohydrate metabolism.

In addition, the compounds of the invention are suitable for treatment and/or prevention of disorders of the urogenital system, for example benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), incontinence, for example mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence or overflow urinary incontinence (MUI, UUI, SUI, OUI), pelvic pain, and also erectile dysfunction and female sexual dysfunction.

The compounds of the invention are further suitable for treatment and/or prevention of inflammatory disorders and autoimmune disorders such as, for example, rheumatoid disorders, inflammatory eye disorders, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary emphysema (e.g. pulmonary emphysema induced by cigarette smoke), cystic fibrosis (CF), sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic intestinal inflammations (IBD, Crohn's disease, ulcerative colitis), pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epidimytitis, oophoritis, salpingitis and vulvovaginitis, and also for the treatment and/or prevention of fibrotic disorders of internal organs such as, for example, the lung, the heart, the kidney, the bone marrow and especially the liver, of dermatological fibroses and of fibrotic disorders of the eye. In the context of the present invention, the term “fibrotic disorders” includes in particular disorders such as hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis, peritoneal fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring, nevi, diabetic retinopathy, proliferative vitroretinopathy and disorders of the connective tissue (for example sarcoidosis). The compounds of the invention can likewise be used for promotion of wound healing, for controlling postoperative scarring, for example following glaucoma operations and cosmetically for ageing or keratinized skin.

In addition, the compounds of the invention can be used for treatment and/or prevention of arteriosclerosis, impaired lipid metabolism and dyslipidaemias (hypolipoproteinaemia, hypertriglyceridaemia, hyperlipidaemia, combined hyperlipidaemias, hypercholesterolaemia, abetalipoproteinaemia, sitosterolaemia), xanthomatosis, Tangier disease, adiposity, obesity, metabolic disorders (metabolic syndrome, hyperglycaemia, insulin-dependent diabetes, non-insulin-dependent diabetes, gestation diabetes, hyperinsulinaemia, insulin resistance, glucose intolerance and diabetic sequelae, such as retinopathy, nephropathy and neuropathy), of anaemias such as haemolytic anaemias, in particular haemoglobinopathies such as sickle cell anaemia and thalassaemias, megaloblastic anaemias, iron deficiency anaemias, anaemias owing to acute blood loss, displacement anaemias and aplastic anaemias, of disorders of the gastrointestinal tract and the abdomen (glossitis, gingivitis, periodontitis, oesophagitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, proctitis, anus pruritis, diarrhoea, coeliac disease, hepatitis, hepatic fibrosis, cirrhosis of the liver, pancreatitis and cholecystitis), of disorders of the central nervous system (stroke, epilepsy, depression), immune disorders, thyroid disorders (hyperthyreosis), skin disorders (psoriasis, acne, eczema, neurodermatitis, various forms of dermatitis, keratitis, bullosis, vasculitis, cellulitis, panniculitis, lupus erythematosus, erythema, lymphomas, skin cancer, Sweet syndrome, Weber-Christian syndrome, scar formation, wart formation, chilblains), of inflammatory eye diseases (saccoidosis, blepharitis, conjunctivitis, iritis, uveitis, chorioiditis, ophthalmitis), of viral diseases (caused by influenza, adeno and corona viruses, for example HPV, HCMV, HIV, SARS), of disorders of the skeletal bone and the joints and also the skeletal muscle, of inflammatory arterial lesions (various forms of arteritis, for example endarteritis, mesarteritis, periarteritis, panarteritis, arteritis rheumatica, arteritis deformans, arteritis temporalis, arteritis cranialis, arteritis gigantocellularis and arteritis granulomatosa, and also Horton syndrome, Churg-Strauss syndrome and Takayasu arteritis), of Muckle-Well syndrome, of Kikuchi disease, of polychondritis, dermatosclerosis and also other disorders having an inflammatory or immunological component, for example cataract, cachexia, osteoporosis, gout, incontinence, leprosy, Sezary syndrome and paraneoplastic syndrome, in the event of rejection reactions after organ transplants and for wound healing and angiogenesis particularly in the case of chronic wounds.

By virtue of their property profile, the compounds of the invention are preferably suitable for treatment and/or prevention of respiratory disorders, in particular of sleep-related respiratory disorders such as obstructive and central sleep apnoeas and also primary and obstructive snoring, for treatment and/or prevention of cardiac arrhythmias and also for treatment and/or prevention of neurodegenerative, neuroinflammatory and neuroimmunological disorders.

The aforementioned well-characterized diseases in humans can also occur with comparable aetiology in other mammals and can likewise be treated therein with the compounds of the present invention.

In the context of the present invention, the term “treatment” or “treating” includes inhibition, retardation, checking, alleviating, attenuating, restricting, reducing, suppressing, repelling or healing of a disease, a condition, a disorder, an injury or a health problem, or the development, the course or the progression of such states and/or the symptoms of such states. The term “therapy” is understood here to be synonymous with the term “treatment”.

The terms “prevention”, “prophylaxis” and “preclusion” are used synonymously in the context of the present invention and refer to the avoidance or reduction of the risk of contracting, experiencing, suffering from or having a disease, a condition, a disorder, an injury or a health problem, or a development or advancement of such states and/or the symptoms of such states.

The treatment or prevention of a disease, a condition, a disorder, an injury or a health problem may be partial or complete.

The present invention thus further provides for the use of the compounds of the invention for treatment and/or prevention of disorders, especially of the aforementioned disorders.

The present invention further provides for the use of the compounds of the invention for production of a medicament for treatment and/or prevention of disorders, especially of the aforementioned disorders.

The present invention further provides a medicament comprising at least one of the compounds of the invention for treatment and/or prevention of disorders, especially of the aforementioned disorders.

The present invention further provides for the use of the compounds of the invention in a method for treatment and/or prevention of disorders, especially of the aforementioned disorders.

The present invention further provides a process for treatment and/or prevention of disorders, especially of the aforementioned disorders, using an effective amount of at least one of the compounds of the invention.

The compounds of the invention can be used alone or, if required, in combination with one or more other pharmacologically active substances, provided that this combination does not lead to undesirable and unacceptable side effects. The present invention therefore further provides medicaments comprising at least one of the compounds of the invention and one or more further drugs, especially for treatment and/or prevention of the aforementioned disorders. Preferred examples of combination active ingredients suitable for this purpose include:

-   -   respiratory stimulants, by way of example and with preference         theophylline, doxapram, nikethamide or caffeine;     -   psychostimulants, by way of example and with preference         modafinil or armodafinil;     -   amphetamines and amphetamine derivatives, by way of example and         with preference amphetamine, metamphetamine or methylphenidate;     -   serotonin reuptake inhibitors, by way of example and with         preference fluoxetine, paroxetine, citalopram, escitalopram,         sertraline, fluvoxamine or trazodone;     -   serotonin precursors, by way of example and with preference         L-tryptophan;     -   selective serotonin noradrenaline reuptake inhibitors, by way of         example and with preference venlafaxine or duloxetine;     -   noradrenergic and specific serotonergic antidepressants, by way         of example and with preference mirtazapine;     -   selective noradrenaline reuptake inhibitors, by way of example         and with preference reboxetine;     -   tricyclic antidepressants, by way of example and with preference         amitriptyline, protriptyline, doxepine, trimipramine,         imipramine, clomipramine or desipramine;     -   alpha2-adrenergic agonists, by way of example and with         preference clonidine;     -   GABA agonists, by way of example and with preference baclofen;     -   alpha sympathomimetics, by way of example and with preference         xylometazoline, oxymetazoline, phenylephrine, naphazoline,         tetryzoline or tramazoline;     -   glucocorticoids, by way of example and with preference         fluticasone, budesonide, beclometasone, mometasone, tixocortol         or triamcinolone;     -   cannabinoid receptor agonists;     -   carboanhydrase inhibitors, by way of example and with preference         acetazolamide, methazolamide or diclofenamide;     -   opioid and benzodiazepine receptor antagonists, by way of         example and with preference flumazenil, naloxone or naltrexone;     -   cholinesterase inhibitors, by way of example and with preference         neostigmine, pyridostigmine, physostigmine, donepezil,         galantamine or rivastigmine;     -   N-methyl-D-aspartate and glutamate antagonists, by way of         example and with preference amantadine, memantine or sabeluzole;     -   nicotine receptor agonists;     -   leukotriene receptor antagonists, by way of example and with         preference montelukast or tipelukast;     -   dopamine receptor antagonists, by way of example and with         preference dromperidone, metoclopramide or benzamide,         butyrophenone or phenothiazine derivatives;     -   appetite suppressants, by way of example and with preference         sibutramine, topiramate, phentermine, lipase inhibitors or         cannabinoid receptor antagonists;     -   proton pump inhibitors, by way of example and with preference         pantoprazole, omeprazole, esomeprazole, lansoprazole or         rabeprazole;     -   organic nitrates and NO donors, for example sodium         nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide         dinitrate, molsidomine or SIN-1, and inhaled NO;     -   compounds which inhibit the degradation of cyclic guanosine         monophosphate (cGMP) and/or cyclic adenosine monophosphate         (cAMP), for example inhibitors of phosphodiesterases (PDE) 1, 2,         3, 4 and/or 5, especially PDE 5 inhibitors such as sildenafil,         vardenafil, tadalafil, udenafil, dasantafil, avanafil,         mirodenafil or lodenafil;     -   NO- and haem-independent activators of soluble guanylate cyclase         (sGC), such as in particular the compounds described in WO         01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462         and WO 02/070510;     -   NO-independent but haem-dependent stimulators of soluble         guanylate cyclase (sGC), such as in particular riociguat,         vericiguat and the compounds described in WO 00/06568, WO         00/06569, WO 02/42301, WO 03/095451, WO 2011/147809, WO         2012/004258, WO 2012/028647 and WO 2012/059549;     -   prostacyclin analogs and IP receptor agonists, by way of example         and with preference iloprost, beraprost, treprostinil,         epoprostenol or selexipag;     -   endothelin receptor antagonists, by way of example and with         preference bosentan, darusentan, ambrisentan or sitaxsentan;     -   compounds which inhibit human neutrophile elastase (HNE), by way         of example and with preference sivelestat or DX-890 (reltran);     -   compounds which inhibit the degradation and alteration of the         extracellular matrix, by way of example and with preference         inhibitors of the matrix metalloproteases (MMPs), especially         inhibitors of stromelysin, collagenases, gelatinases and         aggrecanases (in this context particularly of MMP-1, MMP-3,         MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) and of metalloelastase         (MMP-12);     -   compounds which block the binding of serotonin to its receptors,         by way of example and with preference antagonists of the         5-HT_(2B) receptor such as PRX-08066;     -   antagonists of growth factors, cytokines and chemokines, by way         of example and with preference antagonists of TGF-β, CTGF, IL-1,         IL-4, IL-5, IL-6, IL-8, IL-13 and integrins;     -   Rho kinase-inhibiting compounds, by way of example and with         preference fasudil, Y-27632, SLx-2119, BF-66851, BF-66852,         BF-66853, KI-23095 or BA-1049;     -   compounds which influence the energy metabolism of the heart, by         way of example and with preference etomoxir, dichloroacetate,         ranolazine or trimetazidine;     -   compounds which inhibit the signal transduction cascade, by way         of example and with preference from the group of the kinase         inhibitors, in particular from the group of the tyrosine kinase         and/or serine/threonine kinase inhibitors, by way of example and         with preference nintedanib, dasatinib, nilotinib, bosutinib,         regorafenib, sorafenib, sunitinib, cediranib, axitinib,         telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib,         erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib,         semaxanib or tandutinib;     -   anti-obstructive agents as used, for example, for treatment of         chronic obstructive pulmonary disease (COPD) or bronchial         asthma, by way of example and with preference from the group of         the inhalatively or systemically administered agonists of the         beta-adrenergic receptor (beta-mimetics) and the inhalatively         administered anti-muscarinergic substances;     -   antiinflammatory, immunomodulating, immunosuppressive and/or         cytotoxic agents, by way of example and with preference from the         group of the systemically or inhalatively administered         corticosteroids and also dimethyl fumarate, fingolimod,         glatiramer acetate, β-interferons, natalizumab, teriflunomide,         mitoxantrone, immunoglobulins, acetylcysteine, montelukast,         tipelukast, azathioprine, cyclophosphamide, hydroxycarbamide,         azithromycin, interferon-γ, pirfenidone or etanercept;     -   antifibrotic agents, by way of example and with preference         lysophosphatidic acid receptor 1 (LPA-1) antagonists, CTGF         inhibitors, IL-4 antagonists, IL-13 antagonists, TGF-β         antagonists or pirfenidone;     -   antithrombotic agents, by way of example and with preference         from the group of platelet aggregation inhibitors, the         anticoagulants and the profibrinolytic substances;     -   hypotensive active ingredients, by way of example and with         preference from the group of the calcium antagonists,         angiotensin AII antagonists, ACE inhibitors, vasopeptidase         inhibitors, endothelin antagonists, renin inhibitors, alpha         receptor blockers, beta receptor blockers, mineralocorticoid         receptor antagonists and also the diuretics; and/or     -   active ingredients altering lipid metabolism, for example and         with preference from the group of the thyroid receptor agonists,         cholesterol synthesis inhibitors such as, by way of example and         preferably, HMG-CoA reductase inhibitors or squalene synthesis         inhibitors, the ACAT inhibitors, CETP inhibitors, MTP         inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists,         cholesterol absorption inhibitors, lipase inhibitors, polymeric         bile acid adsorbents, bile acid reabsorption inhibitors and         lipoprotein(a) antagonists.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a beta-adrenergic receptor agonist, by way of example and with preference albuterol, isoproterenol, metaproterenol, terbutalin, fenoterol, formoterol, reproterol, salbutamol or salmeterol.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an antimuscarinergic substance, by way of example and with preference ipratropium bromide, tiotropium bromide or oxitropium bromide.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a corticosteroid, by way of example and with preference prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, betamethasone, beclomethasone, flunisolide, budesonide or fluticasone.

Antithrombotic agents are preferably understood to mean compounds from the group of the platelet aggregation inhibitors, the anticoagulants and the profibrinolytic substances.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a platelet aggregation inhibitor, by way of example and with preference aspirin, clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thrombin inhibitor, by way of example and with preference ximelagatran, melagatran, dabigatran, bivalirudin or clexane.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a GPIIb/IIIa antagonist, by way of example and with preference tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a factor Xa inhibitor, by way of example and with preference rivaroxaban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with heparin or with a low molecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a vitamin K antagonist, by way of example and with preference coumarin.

Hypotensive agents are preferably understood to mean compounds from the group of the calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha receptor blockers, beta receptor blockers, mineralocorticoid receptor antagonists, and the diuretics.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a calcium antagonist, by way of example and with preference nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an alpha-1 receptor blocker, by way of example and with preference prazosin.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a beta receptor blocker, by way of example and with preference propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with an angiotensin AII antagonist, preferred examples being losartan, candesartan, valsartan, telmisartan or embusartan.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an ACE inhibitor, by way of example and with preference enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an endothelin antagonist, by way of example and with preference bosentan, darusentan, ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a renin inhibitor, by way of example and with preference aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a mineralocorticoid receptor antagonist, by way of example and with preference spironolactone, eplerenone or finerenone.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a diuretic, by way of example and with preference furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorphenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

Lipid metabolism modifiers are preferably understood to mean compounds from the group of the CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein(a) antagonists.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a CETP inhibitor, by way of example and with preference torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thyroid receptor agonist, by way of example and with preference D-thyroxine, 3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, by way of example and with preference lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a squalene synthesis inhibitor, by way of example and with preference BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an ACAT inhibitor, by way of example and with preference avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an MTP inhibitor, by way of example and with preference implitapide, BMS-201038, R-103757 or JTT-130.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-gamma agonist, by way of example and with preference pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-delta agonist, by way of example and with preference GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a cholesterol absorption inhibitor, by way of example and with preference ezetimibe, tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipase inhibitor, by way of example and with preference orlistat.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a polymeric bile acid adsorber, by way of example and with preference cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a bile acid reabsorption inhibitor, by way of example and with preference ASBT (=IBAT) inhibitors, for example AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipoprotein(a) antagonist, by way of example and with preference gemcabene calcium (CI-1027) or nicotinic acid.

Particular preference is given to combinations of the compounds of the invention with one or more further active ingredients selected from the group consisting of respiratory stimulants, psychostimulants, serotonin reuptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, sGC stimulators, mineralocorticoid receptor antagonists, antiinflammatory drugs, immunomodulators, immunosuppressives and cytotoxic drugs.

If required, the substances of the invention can also be employed in conjunction with the use of one or more medical technical devices or auxiliaries, provided that this does not lead to unwanted and unacceptable side-effects. Medical devices and auxiliaries suitable for such a combined application are, by way of example and with preference:

-   -   devices for positive airway pressure ventilation, by way of         example and with preference CPAP (continuous positive airway         pressure) devices, BiPAP (bilevel positive airway pressure)         devices and IPPV (intermittent positive pressure ventilation)         devices;     -   neurostimulators of the Nervus hypoglossus;     -   intraoral auxiliaries, by way of example and with preference         protrusion braces;     -   nasal disposable valves;     -   nasal stents.

The present invention further provides medicaments which comprise at least one compound of the invention, typically together with one or more inert, non-toxic, pharmaceutically suitable excipients, and for the use thereof for the aforementioned purposes.

The compounds according to the invention can act systemically and/or locally. For this purpose, they can be administered in a suitable manner, for example by the oral, parenteral, pulmonal, intrapulmonal (inhalative), nasal, intranasal, pharyngeal, lingual, sublingual, buccal, rectal, dermal, transdermal, conjunctival or otic route, or as an implant or stent.

The compounds according to the invention can be administered in administration forms suitable for these administration routes.

Suitable administration forms for oral administration are those which work according to the prior art and release the compounds of the invention rapidly and/or in a modified manner and which contain the compounds of the invention in crystalline and/or amorphized and/or dissolved form, for example tablets (uncoated or coated tablets, for example with gastric juice-resistant or retarded-dissolution or insoluble coatings which control the release of the compound of the invention), tablets or films/oblates which disintegrate rapidly in the oral cavity, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can bypass an absorption step (e.g. take place intravenously, intraarterially, intracardially, intraspinally or intralumbally) or include an absorption (e.g. take place inhalatively, intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). Administration forms suitable for parenteral administration include inter alia preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.

Suitable for the other administration routes are, for example, pharmaceutical forms for inhalation (including powder inhalers, nebulizers, metered aerosols), nasal drops, solutions or sprays, throat sprays, tablets for lingual, sublingual or buccal administration, films/wafers or capsules, suppositories, eye drops, eye ointments or eyewashes, ocular inserts, ear drops, sprays, powders, washes or tampons, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, emulsions, microemulsions, ointments, creams, transdermal therapeutic systems (e.g. patches), milk, pastes, foams, dusting powders, implants or stents.

Preference is given to oral, intravenous, intranasal and pharyngeal administration.

In one embodiment, administration is by the intranasal route. In one embodiment, intranasal administration is effected with the aid of nose drops or a nasal spray. In one embodiment, intranasal administration is effected with the aid of a nasal spray.

The compounds according to the invention can be converted to the administration forms mentioned. This can be done in a manner known per se, by mixing with inert, nontoxic, pharmaceutically suitable excipients. These excipients include

-   -   fillers and carriers (for example cellulose, microcrystalline         cellulose, for example Avicel®, lactose, mannitol, starch,         calcium phosphates, for example Di-Cafos®),     -   ointment bases (for example vaseline, paraffins, triglycerides,         waxes, wool wax, wool wax alcohols, lanolin, hydrophilic         ointment, polyethylene glycols),     -   suppository bases (for example polyethylene glycols, cocoa         butter, hard fat),     -   solvents (e.g. water, ethanol, isopropanol, glycerol, propylene         glycol, mid-chain triglycerides fatty oils, liquid polyethylene         glycols, paraffins),     -   surfactants, emulsifiers, dispersants or wetting agents (for         example sodium dodecylsulfate, lecithin, phospholipids, fatty         alcohols, for example Lanette®, sorbitan fatty acid esters, for         example Span®, polyoxyethylene sorbitan fatty acid esters, for         example Tween®, polyoxyethylene fatty acid glycerides, for         example Cremophor®, polyoxyethylene fatty acid esters,         polyoxyethylene fatty alcohol ethers, glycerol fatty acid         esters, poloxamers, for example Pluronic®),     -   buffer substances, and also acids and bases (for example         phosphates, carbonates, citric acid, acetic acid, hydrochloric         acid, sodium hydroxide, ammonium carbonate, trometamol,         triethanolamine),     -   isotonizing agents (for example glucose, sodium chloride),     -   adsorbents (for example finely divided silicas),     -   viscosity-increasing agents, gel formers, thickeners or binders         (for example polyvinylpyrrolidone, methyl cellulose,         hydroxypropyl cellulose, hydroxypropyl methylcellulose,         carboxymethyl cellulose-sodium, starch, carbomers, polyacrylic         acids, for example Carbopol®, alginates, gelatins),     -   disintegrants (for example modified starch, carboxymethyl         cellulose-sodium, sodium starch glycolate, for example         Explotab®, crosslinked polyvinylpyrrolidone,         croscarmellose-sodium, for example AcDiSol®),     -   flow regulators, lubricants, glidants and mould release agents         (for example magnesium stearate, stearic acid, talc, finely         divided silicas, for example Aerosil®),     -   coating agents (for example sugar, shellac) and film formers for         films or diffusion membranes with fast or modified dissolution         (for example polyvinylpyrrolidones, for example Kollidon®,         polyvinyl alcohol, ethyl cellulose, hydroxypropyl cellulose,         hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose         phthalate, cellulose acetate, cellulose acetate phthalate,         polyacrylates, polymethacrylates, for example Eudragit®),     -   capsule materials (e.g. gelatins, hydroxypropyl methyl         cellulose),     -   natural polymers (for example albumins),     -   synthetic polymers (for example polylactides, polyglycolides,         polyacrylates, polymethacrylates, for example Eudragit®,         polyvinylpyrrolidones, for example Kollidon®, polyvinyl         alcohols, polyvinyl acetates, polyethylene oxides, polyethylene         glycols and the copolymers and block copolymers thereof),     -   plasticizers (for example polyethylene glycols, propylene         glycol, glycerol, triacetin, triacetyl citrate, dibutyl         phthalate),     -   penetrants,     -   stabilizers (e.g. antioxidants, for example ascorbic acid,         sodium ascorbate, ascorbyl palmitate, butylhydroxyanisole,         butylhydroxytoluene, propyl gallate),     -   preservatives (for example parabens, sorbic acid, sodium         benzoate, thiomersal, benzalkonium chloride, chlorhexidine         acetate),     -   dyes (e.g. inorganic pigments, for example iron oxides, titanium         dioxide),     -   aromas, sweeteners, flavour and/or odour correctors.

In general, it has been found to be advantageous in the case of parenteral administration to administer amounts of active compound of about 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight to achieve effective results. In the case of oral administration the dosage is about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and most preferably 0.1 to 10 mg/kg body weight. In the case of intrapulmonary administration, the amount of active compound is generally about 0.1 to 50 mg per inhalation.

In one embodiment, the dosage in the case of intranasal administration is about 0.1 μg to 500 μg per day. In a further embodiment, the dosage in the case of intranasal administration is about 1 μg to 250 μg per day. In a further embodiment, the dosage in the case of intranasal administration is about 1 μg to 120 μg per day. In a further embodiment, the dose of about 0.1 μg to 500 μg per day, or of about 1 μg to 250 μg per day, or of about 1 μg to 120 μg per day, is administered once daily by the intranasal route before sleeping. In one embodiment, the dose of about 0.1 μg to 500 μg per day, or of about 1 μg to 250 μg per day, or of about 1 μg to 120 μg per day, is administered once daily with half to each nostril. In one embodiment, the dose of about 0.1 μg to 500 μg per day, or of about 1 μg to 250 μg per day, or of about 1 μg to 120 μg per day, is administered once daily with half to each nostril before sleeping.

It may nevertheless be necessary in some cases to deviate from the stated amounts of active compounds, specifically as a function of body weight, route of administration, individual response to the active ingredient, nature of the preparation and time or interval over which administration takes place. Thus in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. In the case of administration of greater amounts, it may be advisable to divide them into several individual doses over the day.

The working examples which follow illustrate the invention. The invention is not restricted to the examples.

A. EXAMPLES Abbreviations and Acronyms

-   abs. absolute -   Ac acetyl -   aq. aqueous, aqueous solution -   Boc tert-butoxycarbonyl -   br. broad (in NMR signal) -   Ex. Example -   Bu butyl -   c concentration -   cat. catalytic -   CI chemical ionization (in MS) -   d doublet (in NMR) -   d day(s) -   DCI direct chemical ionization (in MS) -   dd doublet of doublets (in NMR) -   DMF N,N-dimethylformamide -   DMSO dimethyl sulfoxide -   dq doublet of quartets (in NMR) -   dt doublet of triplets (in NMR) -   EI electron impact ionization (in MS) -   eq. equivalent(s) -   ESI electrospray ionization (in MS) -   Et ethyl -   h hour(s) -   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium     hexafluorophosphate -   HOBt 1-hydroxy-1H-benzotriazole hydrate -   HPLC high-pressure, high-performance liquid chromatography -   iPr isopropyl -   conc. concentrated (in the case of a solution) -   LC liquid chromatography -   LC-MS liquid chromatography-coupled mass spectrometry -   lit. literature (reference) -   m multiplet (in NMR) -   Me methyl -   min minute(s) -   MS mass spectrometry -   NMR nuclear magnetic resonance spectrometry -   Ph phenyl -   Pr propyl -   q quartet (in NMR) -   quant. quantitative (in chemical yield) -   RP reverse phase (in HPLC) -   RT room temperature -   R_(t) retention time (in HPLC, LC-MS) -   s singlet (in NMR) -   SFC supercritical liquid chromatography -   t triplet (in NMR) -   tBu tert-butyl -   TFA trifluoroacetic acid -   THF tetrahydrofuran -   UV ultraviolet spectrometry -   v/v volume to volume ratio (of a solution) -   tog. together

LC-MS and HPLC Methods

Method 1 (LC-MS):

Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLC HSS T31.8 μm, 50 mm×1 mm; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% A→1.2 min 5% A→2.0 min 5% A; temperature: 50° C.; flow rate: 0.40 ml/min; UV detection: 208-400 nm.

Method 2 (LC-MS):

MS instrument: Thermo Scientific FT-MS; instrument type UHPLC: Thermo Scientific UltiMate 3000; column: Waters HSS T3 C18 1.8 μm, 75 mm×2.1 mm; mobile phase A: 1 l of water+0.01% formic acid, mobile phase B: 1 l of acetonitrile+0.01% formic acid; gradient: 0.0 min 10% B→2.5 min 95% B→3.5 min 95% B; temperature: 50° C.; flow rate: 0.90 ml/min; UV detection: 210 nm/optimum integration path 210-300 nm.

Method 3 (LC-MS):

MS instrument: Waters Micromass QM; HPLC instrument: Agilent 1100 series; column: Agilent ZORBAX Extend-C18 3.5 μm, 50 mm×3.0 mm; mobile phase A: 1 l of water+0.01 mol of ammonium carbonate, mobile phase B: 1 l of acetonitrile; gradient: 0.0 min 98% A→0.2 min 98% A→3.0 min 5% A→4.5 min 5% A; temperature: 40° C.; flow rate: 1.75 ml/min; UV detection: 210 nm.

Method 4 (LC-MS):

MS instrument: Waters Micromass Quattro Micro; HPLC instrument: Waters UPLC Acquity; column: Waters BEH C18 1.7 μm, 50 mm×2.1 mm; mobile phase A: 1 l of water+0.01 mol of ammonium formate, mobile phase B: 1 l of acetonitrile; gradient: 0.0 min 95% A→0.1 min 95% A→2.0 min 15% A→2.5 min 15% A→2.51 min 10% A→3.0 min 10% A; temperature: 40° C.; flow rate: 0.5 ml/min; UV detection: 210 nm.

Method 5 (LC-MS):

Instrument: Agilent MS Quad 6150 with HPLC Agilent 1290; column: Waters Acquity UPLC HSS T3 1.8 μm, 50 mm×2.1 mm; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% A→0.3 min 90% A→1.7 min 5% A→3.0 min 5% A; flow rate: 1.20 ml/min; temperature: 50° C.; UV detection: 205-305 nm.

Method 6 (LC-MS):

MS instrument: Waters Single Quad MS System; HPLC instrument: Waters UPLC Acquity; column: Waters BEH C18 1.7 μm, 50 mm×2.1 mm; mobile phase A: 1 l of water+1.0 ml of 25% strength ammonia, mobile phase B: 1 l of acetonitrile; gradient: 0.0 min 92% A→0.1 min 92% A→1.8 min 5% A→3.5 min 5% A; temperature: 50° C.; flow rate: 0.45 ml/min; UV detection: 210 nm (208-400 nm).

Method 7 (LC-MS):

MS instrument: Waters SQD; HPLC instrument: Waters UPLC; column: Zorbax SB-Aq (Agilent), 50 mm×2.1 mm, 1.8 μm; mobile phase A: water+0.025% formic acid, mobile phase B: acetonitrile+0.025% formic acid; gradient: 0.0 min 98% A→0.9 min 25% A→1.0 min 5% A→1.4 min 5% A→1.41 min 98% A→1.5 min 98% A; temperature: 40° C.; flow rate: 0.60 ml/min; UV detection: DAD, 210 nm.

Method 8 (Preparative HPLC):

Instrument: Abimed Gilson 305; column: Reprosil C18 10 μm, 250 mm×30 mm; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0-3 min 10% B, 3-27 min 10% B→95% B, 27-34.5 min 95% B, 34.5-35.5 min 95% B→10% B, 35.5-36.5 min 10% B; flow rate: 50 ml/min; room temperature; UV detection: 210 nm.

Method 9 (Preparative HPLC):

Instrument: Waters Prep LC/MS System; column: XBridge C18 5 μm, 100 mm×30 mm; mobile phase A: water, mobile phase B: acetonitrile; gradient profile: 0-2 min 10% B, 2-2.2 min→30% B, 2.2-7 min→70% B, 7-7.5 min→92% B, 7.5-9 min 92% B; flow rate: 65 ml/min+5 ml 2% ammonia in water; room temperature; UV detection: 200-400 nm; at-column injection (complete injection).

Further Details:

The percentages in the example and test descriptions which follow are, unless indicated otherwise, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data for liquid/liquid solutions are based in each case on volume.

Purity figures are generally based on corresponding peak integrations in the LC/MS chromatogram, but may additionally also have been determined with the aid of the ¹H NMR spectrum. If no purity is stated, the purity is generally >95% according to automated peak integration in the LC/MS chromatogram, or the purity has not been determined explicitly.

Stated yields in % of theory are generally corrected for purity if a purity of <100% is indicated. In solvent-containing or contaminated batches, the formal yield may be “>100%”; in these cases the yield is not corrected for solvent or purity.

In cases where the reaction products were obtained by trituration, stirring or recrystallization, it was frequently possible to isolate further amounts of product from the respective mother liquor by chromatography. However, a description of this chromatography is dispensed with hereinbelow unless a large part of the total yield could only be isolated in this step.

Melting points and melting ranges, if stated, are uncorrected.

The descriptions of the coupling patterns of ¹H NMR signals that follow have in some cases been taken directly from the suggestions of the ACD SpecManager (ACD/Labs Release 12.00, Product version 12.5) and have not necessarily been strictly scrutinized. In some cases, the suggestions of the SpecManager were adjusted manually. Manually adjusted or assigned descriptions are generally based on the optical appearance of the signals in question and do not necessarily correspond to a strict, physically correct interpretation. In general, the stated chemical shift refers to the centre of the signal in question. In the case of broad multiplets, an interval is given. Signals obscured by solvent or water were either tentatively assigned or have not been listed.

The ¹H NMR data of synthesis intermediates and working examples can also be stated in the form of ¹H NMR peak lists. Here, for each signal peak, first the δ value in ppm and then the signal intensity in round brackets are listed. The δ value/signal intensity number pairs of different signal peaks are listed separated by commas; accordingly, the peak list for a compound has the form: δ₁ (intensity₁), δ₂ (intensity₂), . . . , δ_(i) (intensity_(i)), . . . , δ_(n) (intensity_(n)).

The intensity of sharp signals correlates with the height of the signals (in cm) in a printed example of an NMR spectrum and shows the true ratios of the signal intensities in comparison with other signals. In the case of broad signals, several peaks or the middle of the signal and their relative intensity may be given in comparison to the most intense signal in the spectrum. The lists of the ¹H NMR peaks are similar to the conventional ¹H NMR printouts and thus usually contain all peaks listed in a conventional NMR interpretation. In addition, like classic ¹H NMR printouts, they may comprise solvent signals, signals of stereoisomers of the target compound in question, peaks of impurities, ¹³C satellite peaks and/or rotation side bands. Peaks of stereoisomers of the target compound and/or peaks of impurities usually have a lower intensity on average than the peaks of the target compound (for example with a purity of >90%). Such stereoisomers and/or impurities may be typical of the particular preparation process. Their peaks can thus help in identifying reproduction of the preparation process with reference to “by-product fingerprints”. An expert calculating the peaks of a target compound by known methods (MestreC, ACD simulation, or using empirically determined expected values) can, if required, isolate the peaks of the target compound, optionally using additional intensity filters. This isolation would be similar to the peak picking in question in conventional ¹H NMR interpretation.

A detailed description of the presentation of NMR data in the form of peak lists can be found in the publication “Citation of NMR Peaklist Data within Patent Applications” (see http://www.researchdisclosure.com/searching-disclosures, Research Disclosure Database Number 605005, 2014, 1 Aug. 2014). In the peak picking routine described in the stated Research Disclosure, the parameter “MinimumHeight” can be set between 1% and 4%. However, depending on the type of chemical structure and/or on the concentration of the compound to be analysed, it may also be advisable to set the parameter “MinimumHeight” to values of <1%.

All reactants or reagents whose preparation is not described explicitly hereinafter were purchased commercially from generally accessible sources. For all other reactants or reagents whose preparation is likewise not described hereinafter and which were not commercially obtainable or were obtained from sources which are not generally accessible, a reference is given to the published literature in which their preparation is described.

Starting Compounds and Intermediates Example 1A 2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidine

Sodium bicarbonate (10.8 g, 128 mmol) was added to a solution of 2-bromo-1-(4-chlorophenyl)ethanone (20.0 g, 85.7 mmol) and pyrimidin-2-amine (8.96 g, 94.2 mmol) in 200 ml of ethanol, and the mixture was stirred at 80° C. for 5 hours. The batch was then cooled to 0° C. (ice bath). The resulting precipitate was filtered off and washed twice with an ethanol/water mixture (1:1). The solid was then dried under reduced pressure at 40° C. overnight. This gave 15.9 g (69.23 mmol, 80.8% of theory) of the target product.

LC-MS (Method 2): R_(t)=1.25 min; m/z=230 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 7.07 (dd, 1H), 7.53 (d, 2H), 8.03 (d, 2H), 8.41 (s, 1H), 8.54 (dd, 1H), 8.97 (dd, 1H).

Example 2A 2-(4-Isopropylphenyl)imidazo[1,2-a]pyrimidine

Sodium bicarbonate (0.52 g, 6.22 mmol) was added to a solution of 2-bromo-1-(4-isopropylphenyl)ethanone (1.0 g, 4.15 mmol) and pyrimidin-2-amine (0.43 g, 4.6 mmol) in 50 ml of ethanol, and the mixture was stirred at 80° C. for 5 hours. The mixture was then concentrated to dryness. The residue was stirred with diethyl ether and the solid that remained was filtered off and dried at 40° C. under reduced pressure overnight. This gave 1.15 g of the crude target product, which was used in subsequent reactions without further purification.

LC-MS (Method 2): R_(t)=1.48 min; m/z=238 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 1.24 (d, 6H), 2.87-3.00 (m, 1H), 7.04 (dd, 1H), 7.34 (d, 2H), 7.92 (d, 2H), 8.33 (s, 1H), 8.51 (dd, 1H), 8.95 (dd, 1H).

Analogously to Examples 1A and 2A, the following compound was prepared from the starting materials specified:

Example Name/Structure/Starting materials Analytical data 3A

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 7.07 (dd, 1H), 7.67 (d, 2H), 7.97 (d, 2H), 8.42 (s, 1H), 8.54 (dd, 1H), 8.97 (dd, 1H). LC-MS (Method 2): R_(t) = 1.34 min; m/z = 274/276 (M + H)⁺.

Example 4A 2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde

300 ml of DMF were initially charged and cooled to 0° C. Phosphorus oxychloride (16 ml, 173 mmol) was then slowly added dropwise. The solution was then slowly warmed to room temperature and stirred at this temperature for another hour. 2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidine (15.9 g, 69.2 mmol) was then added a little at a time. After the addition had ended, the reaction mixture was heated to 80° C. and stirred at this temperature for 1 hour. The batch was then cooled to 0° C. (ice bath). The resulting solid was filtered off with suction, washed repeatedly with water and dried in a high-vacuum drying cabinet at 40° C. overnight. This gave 13.75 g (53.36 mmol, 77% of theory) of the target product.

LC-MS (Method 2): R_(t)=1.44 min; m/z=258 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.46 (dd, 1H), 7.65 (d, 2H), 8.01 (d, 2H), 8.91 (dd, 1H), 9.83 (dd, 1H), 10.07 (s, 1H).

Example 5A 2-(4-Isopropylphenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde

50 ml of DMF were initially charged and cooled to 0° C. Phosphorus oxychloride (2.86 ml, 30.66 mmol) was then slowly added dropwise. The solution was then slowly warmed to room temperature and stirred at this temperature for another hour. 2-(4-Isopropylphenyl)imidazo[1,2-a]pyrimidine (2.91 g, 12.26 mmol) was then added a little at a time. After the addition had ended, the reaction mixture was heated to 80° C. and stirred at this temperature for 1 hour. The batch was then cooled to 0° C. (ice bath). The solid obtained was filtered off with suction and dried under reduced pressure. The resulting crude product was subsequently purified twice by column chromatography (Biotage Isolera, Biotage SNAP-KP-NH column, mobile phase cyclohexane/ethyl acetate gradient). This gave 3 g (11.3 mmol, 92% of theory) of the target compound.

LC-MS (Method 2): R_(t)=1.75 min; m/z=266 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.27 (d, 6H), 2.92-3.07 (m, 1H), 7.39-7.52 (m, 3H), 7.90 (d, 2H), 8.89 (dd, 1H), 9.83 (dd, 1H), 10.08 (s, 1H).

Analogously to Examples 4A and 5A, the following compound was prepared from the starting material specified:

Example Name/Structure/Starting material Analytical data 6A

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 7.46 (dd, 1H), 7.79 (d, 2H), 7.94 (d, 2H), 8.91 (dd, 1H), 9.83 (dd, 1H), 10.07 (s, 1H). LC-MS (Method 1): R_(t) = 0.78 min; m/z = 302/304 (M + H)⁺.

Example 7A 7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride

With stirring, 12 ml of a 4 M solution of hydrogen chloride in dioxane were added to tert-butyl 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (1.52 g, 3.23 mmol). The mixture was stirred at room temperature overnight. The solids obtained were then filtered off with suction, washed repeatedly with diethyl ether and dried under high vacuum at 40° C. This gave 1.76 g of the target product.

LC-MS (Method 2): R_(t)=0.71 min; m/z=370 (M+H)⁺.

Example 8A 7-{[2-(4-Isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride

With stirring, 2.2 ml of a 4 M solution of hydrogen chloride in dioxane were added to tert-butyl 7-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (420 mg, 0.88 mmol). The mixture was stirred at room temperature overnight. The solids obtained were then filtered off with suction, washed repeatedly with diethyl ether and dried under high vacuum at 40° C. This gave 430 mg of the target product.

LC-MS (Method 2): R_(t)=0.87 min; m/z=378 (M+H)⁺.

Example 9A 2-(4-Chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride

With stirring, 15 ml of a 4 M solution of hydrogen chloride in dioxane were added to tert-butyl 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.72 g, 6.00 mmol). The mixture was stirred at room temperature overnight. The solids obtained were then filtered off with suction, washed repeatedly with diethyl ether and dried under high vacuum at 40° C. This gave 3.5 g of the target product.

LC-MS (Method 6): R_(t)=1.36 min; m/z=354 (M+H)⁺.

Example 10A 3-(3,8-Diazabicyclo[3.2.1]oct-3-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride

With stirring, 2.57 ml of a 4 M solution of hydrogen chloride in dioxane were added to tert-butyl 3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (493 mg, 1.03 mmol). The mixture was stirred at room temperature overnight. The reaction solution was then concentrated to dryness and the resulting residue was dried under high vacuum at 40° C. This gave 393 mg of the target product.

LC-MS (Method 2): R_(t)=0.93 min; m/z=362 (M+H)⁺.

Example 11A 2-(4-Chlorophenyl)-3-(2,5-diazabicyclo[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 1)

With stirring, 7.1 ml of a 4 M solution of hydrogen chloride in dioxane were added to tert-butyl 5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Enantiomer 1; 1.29 g, 2.84 mmol). The mixture was stirred at room temperature overnight. The solids obtained were then filtered off with suction, washed repeatedly with diethyl ether and dried under high vacuum at 40° C. This gave 1.4 g of the target product.

LC-MS (Method 2): R_(t)=0.79 min; m/z=354 (M+H)⁺.

Example 12A 2-(4-Chlorophenyl)-3-(2,5-diazabicyclo[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 2)

With stirring, 3.9 ml of a 4 M solution of hydrogen chloride in dioxane were added to tert-butyl 5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Enantiomer 2; 710 mg, 1.56 mmol). The mixture was stirred at room temperature overnight. The solids obtained were then filtered off with suction, washed repeatedly with diethyl ether and dried under high vacuum at 40° C. This gave 740 mg of the target product.

LC-MS (Method 1): R_(t)=0.49 min; m/z=354 (M+H)⁺.

Example 13A 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 1)

With stirring, 4.2 ml of a 4 M solution of hydrogen chloride in dioxane were added to tert-butyl 5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Enantiomer 1; 774 mg, 1.88 mmol). The mixture was stirred at room temperature overnight. The solids obtained were then filtered off with suction, washed repeatedly with diethyl ether and dried under high vacuum at 40° C. This gave 850 mg of the target product.

LC-MS (Method 1): R_(t)=0.54 min; m/z=362 (M+H)⁺.

Example 14A 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 2)

With stirring, 4.0 ml of a 4 M solution of hydrogen chloride in dioxane were added to tert-butyl 5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Enantiomer 2; 734 mg, 1.59 mmol). The mixture was stirred at room temperature overnight. The solids obtained were then filtered off with suction, washed repeatedly with diethyl ether and dried under high vacuum at 40° C. This gave 761 mg of the target product.

LC-MS (Method 1): R_(t)=0.55 min; m/z=362 (M+H)⁺.

Example 15A 1-[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]ethanol (racemate)

2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (500 mg, 1.94 mmol) was suspended in 5 ml of THF. Subsequently, with ice cooling, methylmagnesium bromide in diethyl ether (3.0 M, 710 μl, 2.1 mmol) was added and the mixture was stirred at room temperature for 1 h. Then, a further 4 ml of THF and more methylmagnesium bromide in diethyl ether (3.0 M, 237 μl, 0.7 mmol) were added. The mixture was stirred at room temperature overnight. Aqueous ammonium chloride solution was then added, followed by water and ethyl acetate. The resulting organic phase was separated off, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure on a rotary evaporator. The residue was stirred in diethyl ether. The solid that remained was filtered off with suction and dried in a high-vacuum drying cabinet at 40° C. overnight. This gave 370 mg (1.35 mmol, 70% of theory) of the target product.

LC-MS (Method 2): R_(t)=1.22 min; m/z=274 (M+H)⁺.

Example 16A 2-(4-Chlorophenyl)-3-[1-(3,8-diazabicyclo[3.2.1]oct-3-yl)ethyl]imidazo[1,2-a]pyrimidine dihydrochloride (racemate)

With stirring, 0.21 ml of a 4 M solution of hydrogen chloride in dioxane and 0.2 ml of dioxane were added to tert-butyl 3-{1-[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]ethyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (racemate; 39.8 mg, 0.09 mmol). The mixture was stirred at room temperature overnight. The reaction solution was then concentrated to dryness and the resulting residue was dried under high vacuum at 40° C. This gave 41 mg of the target product.

LC-MS (Method 2): R_(t)=0.86 min; m/z=256/258 (M+H)⁺.

Analogously to Examples 7A-14A, the following compounds were prepared from the starting material specified in each case:

Example Name/Structure/Starting material Analytical data 17A

LC-MS (Method 6): R_(t) = 1.65 min; m/z = 398/400 (M + H)⁺. 18A

LC-MS (Method 6): R_(t) = 1.56 min; m/z = 398/400 (M + H)⁺.

Example 19A 2-(4-Cyclopropylphenyl)-3-(3,8-diazabicyclo[3.2.1]octan-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride

tert-Butyl 3-{[2-(4-cyclopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (720 mg, 1.57 mmol) was dissolved in 3 ml of dioxane, and 3.92 ml of a 4 M solution of hydrogen chloride in dioxane were added with stirring. The mixture was stirred at room temperature overnight. The reaction solution was then concentrated to dryness and the resulting residue was dried under high vacuum at 40° C. This gave 808 mg of the target product.

LC-MS (Method 1): R_(t)=0.48 min; m/z=360 (M+H)⁺.

Working Examples Example 1 tert-Butyl 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate

Under argon and at room temperature, 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (1.50 g, 5.82 mmol) was dissolved in 25 ml of THF, and tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (1.59 g, 6.99 mmol) and acetic acid (670 μl, 12 mmol) were added. Sodium triacetoxyborohydride (1.85 g, 8.73 mmol) was then added a little at a time, and the reaction solution was stirred at room temperature overnight. Then water was gradually and carefully added dropwise (caution: evolution of gas), and subsequently ethyl acetate was added. The resulting organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure on a rotary evaporator. The residue obtained was crystallized from diethyl ether. The crystals formed were filtered off with suction and dried in a high-vacuum drying cabinet at 40° C. overnight. This gave 1.52 g (3.23 mmol, 56% of theory) of the target compound.

LC-MS (Method 2): R_(t)=1.65 min; m/z=470/472 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.40 (s, 9H), 2.42 (br. d, 2H), 2.87 (br. d, 2H), 3.57 (br. d, 2H), 3.72 (br. dd, 2H), 3.84 (br. d, 2H), 3.92 (s, 2H), 7.08 (dd, 1H), 7.55 (d, 2H), 7.96 (d, 2H), 8.58 (dd, 1H), 9.28 (dd, 1H).

Example 2 tert-Butyl 7-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate

Under argon and at room temperature, 2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (500 mg, 1.89 mmol) was dissolved in 10 ml of THF, and tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (516 mg, 2.26 mmol) and acetic acid (220 μl, 3.77 mmol) were added. Sodium triacetoxyborohydride (599 mg, 2.83 mmol) was then added a little at a time, and the reaction solution was stirred at room temperature overnight. Then water was gradually and carefully added dropwise (caution: evolution of gas), and subsequently ethyl acetate was added. The resulting organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure on a rotary evaporator. The residue obtained was purified by column chromatography (Biotage Isolera, Biotage SNAP-KP-NH column; mobile phase: cyclohexane/ethyl acetate gradient). This gave 431 mg (0.9 mmol, 48% of theory) of the target compound.

LC-MS (Method 2): R_(t)=1.79 min; m/z=478 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.25 (d, 6H), 1.40 (s, 9H), 2.39 (br. d, 2H), 2.87 (br. d, 2H), 2.90 (m, 1H), 3.57 (br. d, 2H), 3.72 (br. dd, 2H), 3.84 (br. d, 2H), 3.95 (s, 2H), 7.05 (dd, 1H), 7.36 (d, 2H), 7.80 (d, 2H), 8.55 (dd, 1H), 9.27 (dd, 1H).

Example 3 tert-Butyl 5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (racemate)

Under argon and at room temperature, 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (4.00 g, 15.5 mmol) was dissolved in 100 ml of THF, and tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (3.95 g, 18.6 mmol) and acetic acid (1.8 ml, 31 mmol) were added. Sodium triacetoxyborohydride (4.93 g, 23.3 mmol) was then added a little at a time, and the reaction solution was stirred at room temperature overnight. Further tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (1.6 g, 7.76 mmol) and sodium triacetoxyborohydride (1.2 g, 5.8 mmol) were then added and the reaction solution was once more stirred at room temperature overnight. Then water was gradually and carefully added dropwise (caution: evolution of gas), and subsequently ethyl acetate was added. The resulting organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure on a rotary evaporator. The residue obtained was purified by column chromatography (Biotage Isolera, Biotage SNAP-KP-NH column; mobile phase: cyclohexane/ethyl acetate gradient). This gave 3.17 g (6.7 mmol, 43% of theory) of the target compound.

LC-MS (Method 2): R_(t)=1.55 min; m/z=454/456 (M+H)⁺.

Example 4 and Example 5 tert-Butyl 5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Enantiomers 1 and 2)

3.17 g (6.70 mmol) of racemic tert-butyl 5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Example 3) were separated into the enantiomers by preparative SFC-HPLC on a chiral phase [column: Daicel Chiralpak OJ-H, 5 μm, 250 mm×30 mm; mobile phase: carbon dioxide/ethanol 85:15 (v/v); flow rate: 150 ml/min; pressure: 135 bar; UV detection: 210 nm; temperature: 38° C.]:

Example 4 (Enantiomer 1)

Yield: 1.29 g

R_(t)=4.15 min; chemical purity >99%; >99% ee [column: Daicel Chiralpak OJ-H, 3 μm, 100 mm×4.6 mm; mobile phase: carbon dioxide/ethanol 85:15 (v/v); flow rate: 3 ml/min; pressure: 130 bar; temperature: 40° C.; UV detection: 210 nm].

LC-MS (Method 2): R_(t)=1.55 min; m/z=454/456 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.36 (d, 9H), 1.42-1.55 (m, 1H), 1.57-1.73 (m, 2H), 1.79-1.92 (m, 1H), 2.63-2.80 (m, 3H), 3.09-3.17 (m, 1H), 3.47-3.56 (m, 1H), 3.80 (br. d, 1H), 4.18-4.29 (m, 2H), 7.12 (dd, 1H), 7.56 (d, 2H), 7.84-7.93 (m, 2H), 8.59 (dd, 1H), 9.02 (br. d, 1H).

Example 5 (Enantiomer 2)

Yield: 720 mg

R_(t)=6.6 min; chemical purity >99%; >99% ee

[column: Daicel Chiralpak OJ-H, 3 μm, 100 mm×4.6 mm; mobile phase: carbon dioxide/ethanol 85:15 (v/v); flow rate: 3 ml/min; pressure: 130 bar; temperature: 40° C.; UV detection: 210 nm].

LC-MS (Method 2): R_(t)=1.56 min; m/z=454/456 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.36 (d, 9H), 1.43-1.55 (m, 1H), 1.57-1.73 (m, 2H), 1.80-1.92 (m, 1H), 2.63-2.80 (m, 3H), 3.14 (br. dd, 1H), 3.47-3.56 (m, 1H), 3.80 (br. d, 1H), 4.18-4.29 (m, 2H), 7.12 (dd, 1H), 7.56 (d, 2H), 7.84-7.94 (m, 2H), 8.59 (dd, 1H), 9.02 (br. d, 1H).

Example 6 tert-Butyl 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Under argon and at room temperature, 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (1.50 g, 5.82 mmol) was dissolved in 25 ml of THF, and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.48 g, 6.99 mmol) and acetic acid (670 μl, 12 mmol) were added. Sodium triacetoxyborohydride (1.85 g, 8.73 mmol) was then added a little at a time, and the reaction solution was stirred at room temperature overnight. Then water was gradually and carefully added dropwise (caution: evolution of gas), and subsequently ethyl acetate was added. The resulting organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure on a rotary evaporator. The residue obtained was crystallized from diethyl ether. The crystals formed were taken up in acetonitrile and the precipitate that remained was filtered off with suction and dried in a high-vacuum drying cabinet at 40° C. overnight. This gave 840 mg (1.85 mmol, 32% of theory) of the target compound.

LC-MS (Method 2): R_(t)=2.06 min; m/z=454/456 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.39 (s, 9H), 1.64 (br. s, 4H), 2.26 (br. d, 2H), 2.42-2.60 (m, 2H, obscured by DMSO signal), 3.96-4.05 (m, 4H), 7.14 (dd, 1H), 7.56 (d, 2H), 7.95 (d, 2H), 8.59 (dd, 1H), 9.03 (dd, 1H).

Example 7 tert-Butyl 5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (racemate)

Under argon and at room temperature, 2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (1.50 g, 5.65 mmol) was dissolved in 20 ml of THF, and tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (racemate; 1.44 g, 6.78 mmol) and acetic acid (650 μl, 11.31 mmol) were added. Sodium triacetoxyborohydride (1.8 g, 8.48 mmol) was then added a little at a time, and the reaction solution was stirred at room temperature overnight. Then water was gradually and carefully added dropwise (caution: evolution of gas), and subsequently ethyl acetate was added. The resulting organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure on a rotary evaporator. The residue obtained was purified by column chromatography (Biotage Isolera, Biotage SNAP-KP-NH column; mobile phase: cyclohexane/ethyl acetate gradient). This gave 1760 mg (3.81 mmol, 67% of theory) of the target compound.

LC-MS (Method 2): R_(t)=1.71 min; m/z=462 (M+H)⁺.

Example 8 and Example 9 tert-Butyl 5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Enantiomers 1 and 2)

1.66 g (3.59 mmol) of racemic tert-butyl 5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Example 7) were separated into the enantiomers by preparative SFC-HPLC on a chiral phase [column: Daicel Chiralpak OX-H (SFC), 5 μm, 250 mm×30 mm; mobile phase: carbon dioxide/methanol 62:38 (v/v); flow rate: 80 g/min; pressure: 120 bar; UV detection: 210 nm; temperature: 38° C.]:

Example 8 (Enantiomer 1)

Yield: 774 mg

R_(t)=4.91 min; chemical purity >99%; >99% ee

[column: Daicel Chiralpak OX-3 (SFC), 3 μm, 100 mm×4.6 mm; mobile phase: carbon dioxide/ethanol 70:30 (v/v); flow rate: 3 ml/min; pressure: 130 bar; temperature: 40° C.; UV detection: 210 nm].

LC-MS (Method 1): R_(t)=0.85 min; m/z=462 (M+H)⁺.

[α]_(D) ²⁰=+16.21° (c=0.270, Methanol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.25 (d, 6H), 1.36 (2s, 9H), 1.44-1.56 (m, 1H), 1.66 (br. s, 2H), 1.79-1.95 (m, 1H), 2.65-2.83 (m, 3H), 2.89-3.03 (m, 1H), 3.09-3.20 (m, 1H), 3.53 (br. d, 1H), 3.81 (br. d, 1H), 4.24 (s, 2H), 7.10 (dd, 1H), 7.37 (d, 2H), 7.78 (dd, 2H), 8.56 (dd, 1H), 8.99 (br. d, 1H).

Example 9 (Enantiomer 2)

Yield: 734 mg

R_(t)=6.88 min; chemical purity >99%; >99% ee

[column: Daicel Chiralpak OX-3 (SFC), 3 μm, 100 mm×4.6 mm; mobile phase: carbon dioxide/ethanol 70:30 (v/v); flow rate: 3 ml/min; pressure: 130 bar; temperature: 40° C.; UV detection: 210 nm].

LC-MS (Method 1): R_(t)=0.85 min; m/z=462 (M+H)⁺.

[α]_(D) ²⁰=−15.67° (c=0.270, Methanol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.25 (d, 6H), 1.36 (2s, 9H), 1.44-1.56 (m, 1H), 1.66 (br. s, 2H), 1.79-1.94 (m, 1H), 2.64-2.83 (m, 3H), 2.95 (dt, 1H), 3.09-3.20 (m, 1H), 3.53 (br. d, 1H), 3.81 (br. d, 1H), 4.24 (s, 2H), 7.10 (dd, 1H), 7.37 (d, 2H), 7.78 (dd, 2H), 8.56 (dd, 1H), 8.99 (br. d, 1H).

Example 10 tert-Butyl 3-{1-[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]ethyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (racemate)

1-[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]ethanol (473 mg, 1.73 mmol) and triphenylphosphine (906 mg, 3.46 mmol) were initially charged in 10 ml of dichloromethane, and carbon tetrabromide (1.15 g, 3.46 mmol) was added a little at a time with cooling (ice bath). Triethylamine (480 μl, 3.5 mmol) was then added, and the mixture was stirred at room temperature for 1 h. The mixture was then concentrated by evaporation and the residue was dissolved in 10 ml of acetonitrile. tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (734 mg, 3.46 mmol) was added, and the reaction mixture was stirred at 40° C. overnight. The mixture was then once more concentrated to dryness. 400 mg of the residue obtained in this manner were directly separated into the components by preparative HPLC (Method 8). The remainder of the residue was applied to silica gel and pre-purified by column chromatography (Biotage Isolera, Biotage SNAP-KP-NH column, mobile phase cyclohexane/ethyl acetate gradient). The product thus pre-purified was then re-purified by preparative HPLC (Method 8). This gave 50 mg (0.11 mmol, 6% of theory) of the title compound.

LC-MS (Method 2): R_(t)=2.14 min; MS (ESIpos): m/z=468/470 [M+H]⁺.

Analogously to Examples 1-3 and 6-7, the following compounds were prepared from the starting materials specified in each case:

Example Name/Structure/Starting materials Analytical data 11

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.149 (0.44), −0.008 (3.64), 0.008 (3.55), 0.146 (0.45), 1.345 (14.48), 1.374 (16.00), 1.402 (4.45), 1.489 (0.55), 1.654 (0.95), 1.859 (0.54), 2.328 (0.58), 2.670 (1.91), 2.709 (1.58), 2.774 (0.64), 3.118 (0.57), 3.146 (0.65), 3.155 (0.60), 3.515 (0.56), 3.774 (0.61), 3.827 (0.68), 4.235 (4.16), 5.754 (5.06), 7.108 (1.24), 7.119 (1.32), 7.125 (1.31), 7.136 (1.29), 7.679 (3.52), 7.700 (4.83), 7.812 (1.99), 7.824 (1.97), 7.833 (1.62), 7.845 (1.39), 8.579 (1.48), 8.584 (1.62), 8.590 (1.53), 8.594 (1.45), 9.013 (1.24), 9.030 (1.21). LC-MS (Method 2): R_(t) = 1.68 min; m/z = 498/500 (M + H)⁺. 12

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.39 (s, 9H), 1.56-1.73 (m, 4H), 2.26 (br. d, 2H), 2.46- 2.60 (m, 2H, obscured by DMSO signal), 3.98 (s, 2H), 4.02 (br. s, 2H), 7.14 (dd, 1H), 7.70 (d, 2H), 7.88 (d, 2H), 8.59 (dd, 1H), 9.03 (dd, 1H). LC-MS (Method 5): R_(t) = 1.42 min; m/z = 498/500 (M + H)⁺.

Example 13 (7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)(6-methoxypyridin-2-yl)methanone

6-Methoxypyridine-2-carboxylic acid (35.1 mg, 230 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 μmol) was added and the mixture was stirred at room temperature for 30 min. 7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N-diisopropylethylamine (180 μl, 1.0 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 74 mg (0.15 mmol, 70% of theory) of the title compound were obtained.

LC-MS (Method 2): R_(t)=1.48 min; m/z=505/507 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=2.46-2.66 (m, 2H, partially obscured by DMSO signal), 2.91 (br. d, 1H), 3.05 (br. d, 1H), 3.66-3.83 (m, 3H), 3.80 (s, 3H), 3.89 (d, 1H), 3.93-4.03 (m, 2H), 4.20 (br. s, 1H), 4.44 (br. s, 1H), 6.93 (d, 1H), 7.09 (dd, 1H), 7.29 (d, 1H), 7.54 (d, 2H), 7.83 (t, 1H), 7.97 (d, 2H), 8.58 (dd, 1H), 9.28 (dd, 1H).

Example 14 (3-Chloro-6-methoxypyridin-2-yl)(7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)methanone

3-Chloro-6-methoxypyridine-2-carboxylic acid (43.1 mg, 230 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 μmol) was added and the mixture was stirred at room temperature for 30 min. 7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N-diisopropylethylamine (180 μl, 1.0 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 78 mg (0.15 mmol, 70% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.86 min; m/z=539/541 (M+H)⁺.

Example 15 (7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone

3-Fluoro-6-methoxypyridine-2-carboxylic acid (39.3 mg, 230 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 μmol) was added and the mixture was stirred at room temperature for 30 min. 7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N-diisopropylethylamine (180 μl, 1.0 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 82 mg (0.16 mmol, 76% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.82 min; m/z=523/525 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=2.45-2.60 (m, 2H, obscured by DMSO signal), 2.90 (br. d, 1H), 3.05 (br. d, 1H), 3.58-3.70 (m, 3H), 3.72-3.84 (m, 1H), 3.80 (s, 3H), 3.89 (d, 1H), 3.98 (s, 2H), 4.45 (br. s, 1H), 6.97 (dd, 1H), 7.08 (dd, 1H), 7.55 (d, 2H), 7.80 (t, 1H), 7.97 (d, 2H), 8.58 (dd, 1H), 9.28 (dd, 1H).

Example 16 (7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)[6-(methylsulfanyl)pyridin-2-yl]methanone

6-(Methylsulfanyl)pyridine-2-carboxylic acid (38.8 mg, 230 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 μmol) was added and the mixture was stirred at room temperature for 30 min. 7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N-diisopropylethylamine (180 μl, 1.0 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 84 mg (0.16 mmol, 77% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.85 min; m/z=521/523 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=2.46 (s, 3H), 2.56-2.65 (m, 2H), 2.91 (br. d, 1H), 3.06 (br. d, 1H), 3.65-3.81 (m, 3H), 3.86-4.03 (m, 3H), 4.15 (br. s, 1H), 4.46 (br. s, 1H), 7.09 (dd, 1H), 7.40 (dd, 2H), 7.55 (d, 2H), 7.77 (t, 1H), 7.98 (d, 2H), 8.58 (dd, 1H), 9.28 (dd, 1H).

Example 17 (7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)(cyclopentyl)methanone

Cyclopentanecarboxylic acid (18 μl, 230 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 μmol) was added and the mixture was stirred at room temperature for 30 min. 7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N-diisopropylethylamine (180 μl, 1.0 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 72 mg (0.15 mmol, 74% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.81 min; m/z=466/468 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.43-1.81 (m, 8H), 2.31-2.61 (m, 2H, partially obscured by DMSO signal), 2.86-2.97 (m, 3H), 3.47-3.54 (m, 1H), 3.56-3.63 (m, 1H), 3.77 (dd, 2H), 3.94 (s, 2H), 4.04 (br. s, 1H), 4.32 (br. s, 1H), 7.08 (dd, 1H), 7.55 (d, 2H), 7.97 (d, 2H), 8.59 (dd, 1H), 9.27 (dd, 1H).

Example 18 (3-Fluoro-6-methoxypyridin-2-yl)(7-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)methanone

3-Fluoro-6-methoxypyridine-2-carboxylic acid (39 mg, 0.23 mmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (117 mg, 0.31 mmol) was added and the mixture was stirred at room temperature for 30 min. 7-{[2-(4-Isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N-diisopropylethylamine (180 μl, 1.0 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 83 mg (0.16 mmol, 76% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.84 min; m/z=531 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.26 (d, 6H), 2.46-2.58 (m, 2H, obscured by DMSO signal), 2.86-3.01 (m, 2H), 3.06 (br. d, 1H), 3.57-3.70 (m, 3H), 3.75 (br. d, 1H), 3.79 (s, 3H), 3.89 (d, 1H), 3.99 (s, 2H), 4.46 (br. s, 1H), 6.97 (dd, 1H), 7.06 (dd, 1H), 7.36 (d, 2H), 7.74-7.84 (m, 3H), 8.55 (dd, 1H), 9.26 (dd, 1H).

Example 19 [6-(Difluoromethoxy)pyridin-2-yl](7-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)methanone

6-(Difluoromethoxy)pyridine-2-carboxylic acid (43 mg, 0.23 mmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (117 mg, 0.31 mmol) was added and the mixture was stirred at room temperature for 30 min. 7-{[2-(4-Isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N-diisopropylethylamine (180 μl, 1.0 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 72 mg (0.13 mmol, 61% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.89 min; m/z=549 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.25 (d, 6H), 2.45-2.64 (m, 3H, partially obscured by DMSO signal), 2.86-2.99 (m, 2H), 3.05 (br. d, 1H), 3.65-3.79 (m, 3H), 3.89 (d, 1H), 4.00 (s, 2H), 4.09 (br. s, 1H), 4.44 (br. s, 1H), 7.06 (dd, 1H), 7.21 (d, 1H), 7.36 (d, 2H), 7.54-7.62 (m, 1H), 7.81 (d, 2H), 8.06 (t, 1H), 8.55 (dd, 1H), 9.28 (dd, 1H).

Example 20 (3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)(6-methoxypyridin-2-yl)methanone

6-Methoxypyridine-2-carboxylic acid (36.4 mg, 237 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 μmol) was added and the mixture was stirred at room temperature for 30 min. 2-(4-Chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (100 mg) and N,N-diisopropylethylamine (190 μl, 1.1 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 79 mg (0.16 mmol, 74% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.76 min; m/z=489/491 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.63-1.84 (m, 4H), 2.45 (br. d, 1H), 2.56-2.65 (m, 2H), 2.73 (dd, 1H), 3.77 (s, 3H), 4.00-4.12 (m, 2H), 4.67 (br. d, 2H), 6.93 (d, 1H), 7.15 (dd, 1H), 7.35 (d, 1H), 7.57 (d, 2H), 7.82 (t, 1H), 7.96 (d, 2H), 8.59 (dd, 1H), 9.06 (dd, 1H).

Example 21 (3-Chloro-6-methoxypyridin-2-yl)(3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone

3-Chloro-6-methoxypyridine-2-carboxylic acid (44.5 mg, 237 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 μmol) was added and the mixture was stirred at room temperature for 30 min. 2-(4-Chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (100 mg) and N,N-diisopropylethylamine (190 μl, 1.1 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 56 mg (0.11 mmol, 49% of theory) of the title compound were obtained.

LC-MS (Method 2): R_(t)=1.81 min; m/z=523/524/525 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.62-1.82 (m, 4H), 2.34-2.46 (m, 2H), 2.47-2.59 (m, 1H, obscured by DMSO signal), 2.69-2.78 (m, 1H), 3.62 (br. s, 1H), 3.79 (s, 3H), 4.06 (s, 2H), 4.59 (br. s, 1H), 6.92 (d, 1H), 7.15 (dd, 1H), 7.57 (d, 2H), 7.87 (d, 1H), 7.94 (d, 2H), 8.59 (dd, 1H), 9.04 (dd, 1H).

Example 22 (3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone

3-Fluoro-6-methoxypyridine-2-carboxylic acid (40.6 mg, 237 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (123 mg, 324 μmol) was added and the mixture was stirred at room temperature for 30 min. 2-(4-Chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (100 mg) and N,N-diisopropylethylamine (190 μl, 1.1 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 93 mg (0.18 mmol, 85% of theory) of the title compound were obtained.

LC-MS (Method 2): R_(t)=1.73 min; m/z=507/509 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.62-1.83 (m, 4H), 2.44 (br. t, 2H), 2.48-2.58 (m, 1H, partially obscured by DMSO signal), 2.75 (dd, 1H), 3.76 (s, 3H), 3.92 (br. s, 1H), 4.01-4.12 (m, 2H), 4.61 (br. s, 1H), 6.95 (dd, 1H), 7.14 (dd, 1H), 7.57 (d, 2H), 7.77 (t, 1H), 7.95 (d, 2H), 8.59 (dd, 1H), 9.06 (dd, 1H).

Example 23 (3-Chloro-6-methoxypyridin-2-yl)(5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)methanone (Enantiomer 1)

3-Chloro-6-methoxypyridine-2-carboxylic acid (44.5 mg, 237 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (123 mg, 324 μmol) was added and the mixture was stirred at room temperature for 30 min. 2-(4-Chlorophenyl)-3-(2,5-diazabicyclo[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 1; 100 mg) and N,N-diisopropylethylamine (190 μl, 1.1 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 87 mg (0.16 mmol, 74% of theory) of the title compound were obtained.

LC-MS (Method 2): R_(t)=1.62 min; m/z=523/524/525 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.52-2.00 (m, 4H), 2.57-3.24 (m, 3.75H), 3.35-3.46 (m, 1.25H), 3.70-3.86 (m, 3.75H), 4.20-4.40 (m, 2.25H), 6.84-6.96 (m, 1H), 7.08-7.19 (m, 1H), 7.49-7.61 (m, 2H), 7.79-7.93 (m, 3H), 8.56-8.64 (m, 1H), 8.98-9.07 (m, 1H).

Example 24 (5-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone (Enantiomer 2)

3-Fluoro-6-methoxypyridine-2-carboxylic acid (40.6 mg, 237 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (123 mg, 324 μmol) was added and the mixture was stirred at room temperature for 30 min. 2-(4-Chlorophenyl)-3-(2,5-diazabicyclo[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 2; 100 mg) and N,N-diisopropylethylamine (190 μl, 1.1 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 84 mg (0.17 mmol, 77% of theory) of the title compound were obtained.

LC-MS (Method 6): R_(t)=1.52 min; MS (ESIpos): m/z=507/509 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.50-2.00 (m, 4H), 2.62-2.87 (m, 2.25H), 2.92 (br. s, 0.75H), 3.15 (br. d, 0.25H), 3.38-3.50 (m, 1.5H), 3.56 (br. d, 0.25H), 3.70-3.83 (m, 3.75H), 4.20-4.35 (m, 2H), 4.38 (br. s, 0.25H), 6.89-6.99 (m, 1H), 7.07-7.17 (m, 1H), 7.49-7.60 (m, 2H), 7.70-7.83 (m, 1H), 7.84-7.95 (m, 2H), 8.56-8.63 (m, 1H), 8.99-9.09 (m, 1H).

Example 25 (5-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)(6-methoxy-3-methylpyridin-2-yl)methanone (Enantiomer 1)

6-Methoxy-3-methylpyridine-2-carboxylic acid (39.7 mg, 237 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (123 mg, 324 μmol) was added and the mixture was stirred at room temperature for 30 min. 2-(4-Chlorophenyl)-3-(2,5-diazabicyclo[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 1; 100 mg) and N,N-diisopropylethylamine (190 μl, 1.1 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 25 mg (0.05 mmol, 23% of theory) of the title compound were obtained.

LC-MS (Method 2): R_(t)=1.55 min; MS (ESIpos): m/z=503/505 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.49-1.97 (m, 4H), 2.02-2.12 (m, 3H), 2.58-2.84 (m, 2.25H), 2.91-3.02 (m, 1H), 3.23 (br. s, 0.75H), 3.34-3.45 (m, 1H), 3.65-3.83 (m, 3.75H), 4.19-4.42 (m, 2.25H), 6.71-6.81 (m, 1H), 7.06-7.17 (m, 1H), 7.49-7.65 (m, 3H), 7.82-7.94 (m, 2H), 8.56-8.63 (m, 1H), 8.97-9.08 (m, 1H).

Example 26 (3-Chloro-6-methoxypyridin-2-yl)(5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)methanone (Enantiomer 2)

3-Chloro-6-methoxypyridine-2-carboxylic acid (43 mg, 0.21 mmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (121 mg, 0.32 mmol) was added and the mixture was stirred at room temperature for 30 min. 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 2; 100 mg) and N,N-diisopropylethylamine (190 μl, 1.1 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). This gave 82 mg (0.15 mmol, content 96%, 70% of theory) of the title compound.

LC-MS (Method 2): R_(t)=1.73 min; m/z=531/533 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.20-1.31 (m, 6H), 1.53-2.01 (m, 4H), 2.62 (br. d, 0.75H), 2.69-2.85 (m, 1.5H), 2.89-3.03 (m, 2H), 3.21 (br. s, 0.75H), 3.43 (br. d, 1H), 3.70-3.85 (m, 3.75H), 4.21-4.35 (m, 2H), 4.39 (br. s, 0.25H), 6.85-6.96 (m, 1H), 7.05-7.14 (m, 1H), 7.30-7.43 (m, 2H), 7.70-7.87 (m, 2.75H), 7.90 (d, 0.25H), 8.56 (dd, 1H), 8.95-9.04 (m, 1H).

Example 27 (5-Cyclopropyl-1,3-oxazol-4-yl)(5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)methanone (Enantiomer 2)

5-Cyclopropyl-1,3-oxazole-4-carboxylic acid (32 mg, 0.21 mmol) was dissolved in 1.35 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (109 mg, 0.29 mmol) was added and the mixture was stirred at room temperature for 30 min. 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 2; 90 mg) and N,N-diisopropylethylamine (170 μl, 0.96 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 67 mg (0.14 mmol, 71% of theory) of the title compound were obtained.

LC-MS (Method 2): R_(t)=1.51 min; m/z=497 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.83-0.95 (m, 2H), 0.96-1.08 (m, 2H), 1.25 (d, 6H), 1.51-1.61 (m, 1H), 1.67-1.99 (m, 3H), 2.44-2.57 (m, 0.7H, partially obscured by DMSO signal), 2.57-2.66 (m, 0.3H), 2.73-3.01 (m, 4H), 3.37 (dd, 0.7H), 3.64-3.76 (m, 1H), 4.03 (br. d, 0.3H), 4.23-4.33 (m, 2H), 4.37 (br. s, 0.3H), 4.59 (br. s, 0.7H), 7.06-7.14 (m, 1H), 7.31-7.40 (m, 2H), 7.75-7.83 (m, 2H), 8.12-8.20 (m, 1H), 8.53-8.59 (m, 1H), 8.98-9.06 (m, 1H).

Example 28 (3-Fluoro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone

3-Fluoro-6-methoxypyridine-2-carboxylic acid (39.2 mg, 0.21 mmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 0.31 mmol) was added and the mixture was stirred at room temperature for 30 min. 3-(3,8-Diazabicyclo[3.2.1]oct-3-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (98 mg) and N,N-diisopropylethylamine (180 μl, 1.04 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 65 mg (0.13 mmol, 61% of theory) of the title compound were obtained.

LC-MS (Method 5): R_(t)=1.22 min; MS (ESIpos): m/z=515 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.26 (d, 6H), 1.63-1.86 (m, 4H), 2.44 (br. t, 2H), 2.48-2.60 (m, 1H, partially obscured by DMSO signal), 2.76 (dd, 1H), 2.96 (quin, 1H), 3.76 (s, 3H), 3.92 (br. s, 1H), 4.00-4.11 (m, 2H), 4.61 (br. s, 1H), 6.95 (dd, 1H), 7.12 (dd, 1H), 7.36 (d, 2H), 7.77 (t, 1H), 7.83 (d, 2H), 8.57 (dd, 1H), 9.02 (dd, 1H).

Example 29 (3-Chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone

3-Chloro-6-methoxypyridine-2-carboxylic acid (43 mg, 0.23 mmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (118 mg, 0.31 mmol) was added and the mixture was stirred at room temperature for 30 min. 3-(3,8-Diazabicyclo[3.2.1]oct-3-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (98 mg) and N,N-diisopropylethylamine (180 μl, 1.04 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 67 mg (0.13 mmol, 60% of theory) of the title compound were obtained.

LC-MS (Method 5): R_(t)=1.27 min; MS (ESIpos): m/z=531/533 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.26 (d, 6H), 1.63-1.84 (m, 4H), 2.41 (br. t, 2H), 2.46-2.57 (m, 1H, obscured by DMSO signal), 2.75 (br. d, 1H), 2.96 (quin, 1H), 3.63 (br. s, 1H), 3.79 (s, 3H), 4.00-4.11 (m, 2H), 4.60 (br. s, 1H), 6.92 (d, 1H), 7.12 (dd, 1H), 7.37 (d, 2H), 7.82 (d, 2H), 7.87 (d, 1H), 8.56 (dd, 1H), 9.01 (dd, 1H).

Analogously to Examples 13-29, the following compounds were prepared from the starting materials specified in each case:

Example Name/Structure/Starting materials Analytical data 30

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 2.43 (br. d, 1H), 2.47- 2.59 (m, 1H, partially obscured by DMSO signal), 2.87 (br. d, 1H), 3.02 (br. d, 1H), 3.37 (br. s, 1H), 3.59 (br. d, 1H), 3.65-3.76 (m, 2H), 3.87 (d, 1H), 3.97 (s, 2H), 4.47 (br. s, 1H), 7.08 (dd, 1H), 7.24-7.34 (m, 2H), 7.41-7.53 (m, 2H), 7.55 (d, 2H), 7.95 (d, 2H), 8.58 (dd, 1H), 9.27 (dd, 1H). LC-MS (Method 2): R_(t) = 1.53 min; m/z = 492/494 (M + H)⁺. 31

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 2.46-2.55 (m, 1H, obscured by DMSO signal), 2.59 (br. d, 1H), 2.86 (br. d, 1H), 2.99 (br. d, 1H), 3.54-3.75 (m, 4H), 3.77 (s, 3H), 3.85 (d, 1H), 3.98 (s, 2H), 4.39 (br. s, 1H), 6.91-7.12 (m, 4H), 7.36 (t, 1H), 7.55 (d, 2H), 7.97 (d, 2H), 8.57 (dd, 1H), 9.29 (dd, 1H). LC-MS (Method 2): R_(t) = 1.53 min; m/z = 504/506 (M + H)⁺. 32

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.60-1.79 (m, 4H), 2.25 (br. d, 1H), 2.42 (br. d, 1H), 2.47- 2.60 (m, 1H, partially obscured by DMSO signal), 2.68 (br. d, 1H), 3.66 (br. s, 1H), 4.04 (s, 2H), 4.59 (br. s, 1H), 7.14 (dd, 1H), 7.24- 7.32 (m, 2H), 7.40-7.53 (m, 2H), 7.57 (d, 2H), 7.95 (d, 2H), 8.59 (dd, 1H), 9.04 (dd, 1H). LC-MS (Method 2): R_(t) = 1.73 min; m/z = 476/478 (M + H)⁺. 33

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.64-1.83 (m, 4H), 2.40- 2.63 (m, 3H, partially obscured by DMSO signal), 2.43 (s, 3H), 2.74 (br. d, 1H), 3.99-4.11 (m, 2H), 4.63 (br. s, 2H), 7.15 (dd, 1H), 7.42 (dd, 2H), 7.57 (d, 2H), 7.75 (t, 1H), 7.97 (d, 2H), 8.55-8.62 (m, 1H), 9.06 (d, 1H). LC-MS (Method 2): R_(t) = 1.86 min; m/z = 505/507 (M + H)⁺. 34

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.44-1.66 (m, 7H), 1.66- 1.80 (m, 5H), 2.26 (br. d, 2H), 2.47-2.66 (m, 2H, partially obscured by DMSO signal), 2.80- 2.92 (m, 1H), 3.94-4.06 (m, 2H), 4.28 (br. s, 1H), 4.41 (br. d, 1H), 7.14 (dd, 1H), 7.56 (d, 2H), 7.96 (d, 2H), 8.59 (dd, 1H), 9.05 (dd, 1H). LC-MS (Method 2): R_(t) = 1.83 min; m/z = 450/452 (M + H)⁺. 35

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.63-1.81 (m, 4H), 2.42 (br. d, 1H), 2.47-2.62 (m, 2H, partially obscured by DMSO signal), 2.64-2.75 (m, 1H), 2.67 (d, 3H), 3.97-4.09 (m, 2H), 4.60 (br. s, 1H), 4.76 (br. s, 1H), 6.51 (d, 1H), 6.65 (q, 1H), 6.82 (d, 1H), 7.14 (dd, 1H), 7.44 (t, 1H), 7.56 (d, 2H), 7.96 (d, 2H), 8.59 (dd, 1H), 9.05 (dd, 1H). LC-MS (Method 2): R_(t) = 1.51 min; m/z = 532/534 (M − H + HCOOH)—. 36

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.64-1.80 (m, 4H), 2.30- 2.47 (m, 2H), 2.57-2.74 (m, 2H), 3.78 (s, 3H), 3.92 (br. s, 1H), 4.05 (s, 2H), 4.54 (br. s, 1H), 6.92-7.08 (m, 3H), 7.30 (br. t, 1H), 7.35 (t, 1H), 7.61 (d, 2H), 7.93 (d, 2H), 8.71 (br. d, 1H), 9.15 (br. d, 1H). LC-MS (Method 2): R_(t) = 1.73 min; m/z = 488/490 (M + H)⁺. 37

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.38-1.79 (m, 11H), 1.82- 1.96 (m, 1H), 2.63-2.86 (m, 4H), 3.19 (dd, 0.5H), 3.37 (dd, 0.5H), 3.54 (br. d, 0.5H), 3.75 (br. d, 0.5H), 3.93 (br. d, 0.5H), 4.18- 4.31 (m, 2.5H), 7.12 (dd, 1H), 7.56 (d, 2H), 7.89 (d, 2H), 8.59 (dd, 1H), 9.03 (dt, 1H). LC-MS (Method 2): R_(t) = 1.42 min; m/z = 450/452 (M + H)⁺. 38

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.44-1.99 (m, 4H), 2.61- 2.72 (m, 1H), 2.76-2.84 (m, 1H), 2.90 (br. s, 1H), 3.17 (br. d, 0.25H), 3.37 (br. d, 0.75H), 3.53 (br. s, 0.75H), 3.63 (br. d, 0.25H), 3.69-3.82 (m, 3.75H), 4.21-4.34 (m, 2.25H), 6.80-6.88 (m, 1.5H), 6.94-7.06 (m, 1.5H), 7.08-7.17 (m, 1H), 7.26-7.39 (m, 1H), 7.50-7.61 (m, 2H), 7.86-7.96 (m, 2H), 8.55- 8.63 (m, 1H), 9.00-9.09 (m, 1H). LC-MS (Method 2): R_(t) = 1.46 min; m/z = 488/490 (M + H)⁺. 39

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.47-1.82 (m, 3H), 1.84- 1.98 (m, 1H), 2.46-2.57 (m, 0.75H, obscured by DMSO signal), 2.60-2.87 (m, 2.25H), 2.92 (br. s, 0.75H), 3.02 (br. d, 0.25H), 3.42 (br. d, 1H), 3.77 (br. d, 0.75H), 4.20-4.33 (m, 2H), 4.37 (br. s, 0.25H), 7.09-7.17 (m, 1H), 7.20-7.40 (m, 3H), 7.41-7.61 (m, 3H), 7.83-7.95 (m, 2H), 8.56-8.63 (m, 1H), 8.98-9.08 (m, 1H). LC-MS (Method 2): R_(t) = 1.49 min; m/z = 476/478 (M + H)⁺. 40

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.46-1.99 (m, 4H), 2.63- 2.73 (m, 1H), 2.80-2.94 (m, 2H), 3.39 (dd, 0.75H), 3.48 (br. d, 0.25H), 3.70-3.83 (m, 3.75H), 3.92 (br. d, 0.25H), 3.98 (br. s, 0.75H), 4.24-4.35 (m, 2H), 4.38 (br. s, 0.25H), 6.84-6.94 (m, 1H), 7.08- 7.20 (m, 1.75H), 7.29 (d, 0.25H), 7.49-7.60 (m, 2H), 7.74-7.94 (m, 3H), 8.55-8.62 (m, 1H), 9.00-9.08 (m, 1H). LC-MS (Method 2): R_(t) = 1.41 min; m/z = 489/491 (M + H)⁺. 41

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.49-2.01 (m, 4H), 2.62- 2.87 (m, 2.25H), 2.92 (br. s, 0.75H), 3.15 (br. d, 0.25H), 3.38- 3.50 (m, 1.5H), 3.56 (br. d, 0.25H), 3.69-3.84 (m, 3.75H), 4.20-4.35 (m, 2H), 4.38 (br. s, 0.25H), 6.87-6.99 (m, 1H), 7.08- 7.17 (m, 1H), 7.49-7.59 (m, 2H), 7.70-7.82 (m, 1H), 7.83-7.95 (m, 2H), 8.56-8.63 (m, 1H), 8.98-9.08 (m, 1H). LC-MS (Method 2): R_(t) = 1.51 min; m/z = 507/509 (M + H)⁺. 42

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.48-1.83 (m, 3H), 1.83- 1.98 (m, 1H), 2.46-2.57 (m, 0.75H, obscured by DMSO signal), 2.60-2.88 (m, 2.25H), 2.92 (br. s, 0.75H), 3.02 (br. d, 0.25H), 3.43 (br. d, 1H), 3.77 (br. d, 0.75H), 4.20-4.34 (m, 2H), 4.38 (br. s, 0.25H), 7.08-7.17 (m, 1H), 7.19-7.40 (m, 3H), 7.41-7.60 (m, 3H), 7.83-7.95 (m, 2H), 8.55-8.63 (m, 1H), 8.97-9.08 (m, 1H). LC-MS (Method 2): R_(t) = 1.50 min; m/z = 476/478 (M + H)⁺. 43

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.44-1.99 (m, 4H), 2.61- 2.72 (m, 1H), 2.74-2.84 (m, 1H), 2.90 (br. s, 1H), 3.17 (br. d, 0.25H), 3.37 (br. d, 0.75H), 3.53 (br. s, 0.75H), 3.63 (br. d, 0.25H), 3.67-3.82 (m, 3.75H), 4.18-4.35 (m, 2.25H), 6.76-6.87 (m, 1.5H), 6.92-7.05 (m, 1.5H), 7.08-7.17 (m, 1H), 7.25-7.39 (m, 1H), 7.49-7.61 (m, 2H), 7.84-7.96 (m, 2H), 8.52- 8.63 (m, 1H), 8.98-9.09 (m, 1H). LC-MS (Method 2): R_(t) = 1.46 min; m/z = 488/490 (M + H)⁺. 44

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.46-1.99 (m, 4H), 2.63- 2.74 (m, 1H), 2.80-2.94 (m, 2H), 3.39 (dd, 0.75H), 3.49 (br. d, 0.25H), 3.69-3.83 (m, 3.75H), 3.92 (br. d, 0.25H), 3.98 (br. s, 0.75H), 4.24-4.35 (m, 2H), 4.38 (br. s, 0.25H), 6.84-6.94 (m, 1H), 7.08- 7.20 (m, 1.75H), 7.29 (d, 0.25H), 7.48-7.60 (m, 2H), 7.73-7.95 (m, 3H), 8.54-8.63 (m, 1H), 9.00-9.09 (m, 1H). LC-MS (Method 2): R_(t) = 1.41 min; m/z = 489/491 (M + H)⁺. 45

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.52-2.00 (m, 4H), 2.72 (br. d, 0.75H), 2.73 (br. d, 1H), 2.80 (br. s, 0.5H), 2.94-3.01 (m, 1H), 3.20 (br. s, 0.75H), 3.35-3.47 (m, 1H), 3.70-3.86 (m, 3.75H), 4.20-4.33 (m, 2H), 4.38 (br. s, 0.25H), 6.85-6.97 (m, 1H), 7.08- 7.19 (m, 1H), 7.49-7.61 (m, 2H), 7.79-7.94 (m, 3H), 8.56-8.64 (m, 1H), 8.97-9.08 (m, 1H). LC-MS (Method 2): R_(t) = 1.63 min; MS (ESIpos): m/z = 523/524/525 [M + H]⁺. 46

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.88-0.97 (m, 2H), 1.03- 1.13 (m, 2H), 2.44-2.65 (m, 3H, partially obscured by DMSO signal), 2.92-3.06 (m, 2H), 3.62- 3.73 (m, 2H), 3.77-3.90 (m, 2H), 3.96 (s, 2H), 4.41 (br. s, 1H), 4.75 (br. s, 1H), 7.08 (dd, 1H), 7.54 (d, 2H), 7.98 (d, 2H), 8.20 (s, 1H), 8.59 (dd, 1H), 9.29 (dd, 1H). LC-MS (Method 1): R_(t) = 0.76 min; MS (ESIpos): m/z = 505/507 [M + H]⁺. 47

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.89-0.98 (m, 2H), 1.00- 1.09 (m, 2H), 1.57-1.87 (m, 4H), 2.08-2.18 (m, 1H), 2.30-2.42 (m, 2H), 2.58-2.70 (m, 2H), 4.02 (s, 2H), 4.53 (br. s, 1H), 5.15 (br. s, 1H), 7.15 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.37 (s, 1H), 8.59 (dd, 1H), 9.05 (dd, 1H). LC-MS (Method 2): R_(t) = 1.75 min; MS (ESIpos): m/z = 489/491 [M + H]⁺. 48

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.59-1.84 (m, 4H), 2.35- 2.44 (m, 2H), 2.52 (s, 3H, partially obscured by DMSO signal), 2.60- 2.69 (m, 2H), 4.02 (s, 2H), 4.57 (br. s, 1H), 5.12 (br. s, 1H), 7.14 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.29 (s, 1H), 8.56 (dd, 1H), 9.06 (dd, 1H). LC-MS (Method 2): R_(t) = 1.59 min; MS (ESIpos): m/z = 463/465 [M + H]⁺. 49

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.21 (t, 6H), 1.63-1.82 (m, 4H), 2.39 (br. t, 2H), 2.64 (br. t, 2H), 3.62 (quin, 1H), 4.02 (s, 2H), 4.57 (br. s, 1H), 4.97 (br. s, 1H), 7.15 (dd, 1H), 7.56 (d, 2H), 7.96 (d, 2H), 8.29 (s, 1H), 8.59 (dd, 1H), 9.05 (dd, 1H). LC-MS (Method 2): R_(t) = 1.86 min; MS (ESIpos): m/z = 491/493 [M + H]⁺. 50

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.74 (br. s, 4H), 2.27 (s, 3H), 2.34-2.45 (m, 2H), 2.40 (s, 3H), 2.60-2.70 (m, 2H), 4.04 (s, 2H), 4.58 (br. s, 2H), 7.17 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.59 (dd, 1H), 9.07 (dd, 1H). LC-MS (Method 2): R_(t) = 1.53 min; MS (ESIpos): m/z = 477/479 [M + H]⁺. 51

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.17 (t, 3H), 1.61-1.83 (m, 4H), 2.39 (br. d, 2H), 2.64 (br. d, 2H), 2.95 (q, 2H), 4.02 (s, 2H), 4.57 (br. s, 1H), 5.07 (br. s, 1H), 7.15 (dd, 1H), 7.56 (d, 2H), 7.96 (d, 2H), 8.30 (s, 1H), 8.59 (dd, 1H), 9.05 (dd, 1H). LC-MS (Method 2): R_(t) = 1.73 min; MS (ESIpos): m/z = 477/479 [M + H]⁺. 52

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.67-1.77 (m, 2H), 1.79- 1.91 (m, 2H), 2.39-2.48 (m, 2H), 2.43 (s, 3H), 2.66 (br. d, 1H), 2.72 (br. d, 1H), 4.04 (s, 2H), 4.57 (br. s, 1H), 5.46 (br. s, 1H), 7.15 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.59 (dd, 1H), 9.06 (dd, 1H). LC-MS (Method 1): R_(t) = 1.10 min; MS (ESIpos): m/z = 557/559 [M + H]⁺. 53

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.86-0.99 (m, 2H), 1.02- 1.13 (m, 2H), 1.61-1.85 (m, 4H), 2.36-2.46 (m, 2H), 2.60-2.75 (m, 3H), 4.03 (s, 2H), 4.58 (br. s, 1H), 5.12 (br. s, 1H), 7.15 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.18 (s, 1H), 8.59 (dd, 1H), 9.06 (dd, 1H). LC-MS (Method 1): R_(t) = 0.91 min; MS (ESIpos): m/z = 489/491 [M + H]⁺. 54

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.31 (d, 6H), 1.63-1.85 (m, 4H), 2.40-2.48 (m, 2H), 2.65 (br. d, 2H), 3.23-3.33 (m, 1H, partially obscured by H₂O signal), 4.04 (s, 2H), 4.59 (br. s, 1H), 4.99 (br. s, 1H), 7.14 (dd, 1H), 7.55 (d 2H), 7.96 (d, 2H), 8.06 (s, 1H), 8.59 (dd, 1H), 9.05 (dd, 1H). LC-MS (Method 1): R_(t) = 1.01 min; MS (ESIpos): m/z = 507/509 [M + H]⁺. 55

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.62-1.94 (m, 4H), 2.39- 2.59 (m, 2H, partially obscured by DMSO signal), 2.68 (dd, 2H), 4.06 (s, 2H), 4.37-4.65 (m, 2H), 7.15 (dd, 1H), 7.57 (d, 2H), 7.97 (d, 2H), 8.29 (s, 1H), 8.60 (dd, 1H), 9.07 (dd, 1H), 9.23 (s, 1H). LC-MS (Method 1): R_(t) = 0.77 min; MS (ESIpos): m/z = 465/467 [M + H]⁺. 56

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.60-1.81 (m, 4H), 2.31- 2.42 (m, 2H), 2.36 (s, 3H), 2.47 (s, 3H), 2.63 (br. d, 2H), 4.02 (s, 2H), 4.54 (br. s, 1H), 5.18 (br. s, 1H), 7.14 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.59 (dd, 1H), 9.05 (dd, 1H). LC-MS (Method 5): R_(t) = 1.16 min; MS (ESIpos): m/z = 477/479 [M + H]⁺. 57

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.62-1.77 (m, 4H), 2.21- 2.40 (m, 2H), 2.63 (br. d, 2H), 3.92 (br. s, 1H), 4.04 (s, 2H), 4.10 (s, 3H), 4.51 (br. s, 1H), 7.15 (dd, 1H), 7.57 (d, 2H), 7.93 (d, 2H), 8.59 (dd, 1H), 9.03 (dd, 1H). LC-MS (Method 5): R_(t) = 1.30 min; MS (ESIpos): m/z = 563/565 [M + H]⁺. 58

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.65-1.89 (m, 4H), 2.45 (br. d, 2H), 2.67 (br. t, 2H), 4.05 (s, 2H), 4.61 (br. s, 1H), 4.74 (br. s, 1H), 7.15 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.59 (dd, 1H), 8.62 (s, 1H), 9.06 (dd, 1H). LC-MS (Method 5): R_(t) = 1.31 min; MS (ESIpos): m/z = 533/535 [M + H]⁺. 59

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.63-1.79 (m, 4H), 2.34- 2.45 (m, 2H), 2.46-2.61 (m, 1H, partially obscured by DMSO signal), 2.55 (s, 3H), 2.68 (dd, 1H), 4.04 (s, 2H), 4.34 (br. s, 1H), 4.60 (br. s, 1H), 7.15 (dd, 1H), 7.57 (d, 2H), 7.96 (d, 2H), 8.59 (dd, 1H), 8.89 (s, 1H), 9.06 (dd, 1H). LC-MS (Method 5): R_(t) = 1.11 min; MS (ESIpos): m/z = 479/481 [M + H]⁺. 60

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.68-1.80 (m, 2H), 1.83- 1.95 (m, 2H), 2.45 (br. d, 1H), 2.48-2.57 (m, 1H, partially obscured by DMSO signal), 2.65 (br. d, 1H), 2.80 (br. d, 1H), 4.05 (s, 2H), 4.61 (br. s, 1H), 5.43 (br. s, 1H), 7.15 (dd, 1H), 7.55 (d, 2H), 7.97 (d, 2H), 8.60 (dd, 1H), 8.79 (s, 1H), 9.06 (dd, 1H). LC-MS (Method 2): R_(t) = 2.00 min; MS (ESIpos): m/z = 533/535 [M + H]⁺. 61

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.75 (br. d, 4H), 2.44 (br. t, 2H), 2.66 (br. t, 2H), 4.03 (s, 2H), 4.62 (br. s, 1H), 5.02 (br. s, 1H), 7.14 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.27 (d, 1H), 8.59 (dd, 1H), 9.06 (dd, 1H), 9.15 (d, 1H). LC-MS (Method 5): R_(t) = 1.07 min; MS (ESIpos): m/z = 465/467 [M + H]⁺. 62

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.25 (d, 6H), 1.64-1.81 (m, 4H), 2.41 (br. d, 1H), 2.58 (br. s, 1.75H), 2.65-2.76 (m, 4.25H), 2.88-3.01 (m, 1H), 3.98-4.09 (m, 2H), 4.60 (br. s, 1H), 4.76 (br. s, 1H), 6.51 (d, 1H), 6.65 (q, 1H), 6.80 (d, 1H), 7.12 (dd, 1H), 7.37 (d, 2H), 7.74 (d, 1H), 7.84 (d, 2H), 8.56 (dd, 1H), 9.02 (dd, 1H). LC-MS (Method 2): R_(t) = 1.58 min; MS (ESIpos): m/z = 496 [M + H]⁺. 63

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.25 (d, 6H), 1.66-1.84 (m, 4H), 2.44 (br. d, 1H), 2.56- 2.66 (m, 2H), 2.74 (dd, 1H), 2.95 (quin, 1H), 3.77 (s, 3H), 3.99-4.11 (m, 2H), 4.64 (br. s, 1H), 4.69 (br. s, 1H), 6.93 (d, 1H), 7.12 (dd, 1H), 7.31-7.40 (m, 3H), 7.77-7.88 (m, 3H), 8.57 (dd, 1H), 9.03 (dd, 1H). LC-MS (Method 5): R_(t) = 1.24 min; MS (ESIpos): m/z = 497 [M + H]⁺. 64

H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.26 (d, 6H), 1.64-1.81 (m, 4H), 2.26 (br. d, 1H), 2.42 (br. d, 1H), 2.58 (br. d, 1H), 2.68 (br. d, 1H), 2.96 (quin, 1H), 3.67 (br. s, 1H), 4.04 (s, 2H), 4.59 (br. s, 1H), 7.12 (dd, 1H), 7.23-7.32 (m, 2H), 7.38 (d, 2H), 7.41-7.54 (m, 2H), 7.83 (d, 2H), 8.56 (dd, 1H), 9.01 (dd, 1H). LC-MS (Method 5): R_(t) = 1.23 min; MS (ESIpos): m/z = 484 [M + H]⁺. 65

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.41-1.60 (m, 4H), 1.61- 1.75 (m, 1H), 1.76-1.90 (m, 1H), 2.01 (br. d, 0.5H), 2.06-2.24 (m, 2.5H), 2.34 (br. d, 1H), 3.12 (br. d, 0.5H), 3.23 (br. dd, 0.5H), 3.59 (s, 1.5H), 3.75 (br. d, 0.5H), 3.85 (s, 1.5H), 4.04 (br. d, 0.5H), 4.07- 4.17 (m, 1H), 4.43 (br. d, 0.5H), 4.71 (br. d, 0.5H), 6.89 (dd, 0.5H), 6.98 (dd, 0.5H), 7.08-7.15 (m, 1H), 7.52-7.61 (m, 2H), 7.66-7.84 (m, 3H), 8.53-8.63 (m, 1H), 9.27 (d, 1H). LC-MS (Method 2): R_(t) = 1.77 min; MS (ESIpos): m/z = 521/523 [M + H]⁺. 66

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.25 (d, 6H), 2.44-2.65 (m, 2H, partially obscured by DMSO signal), 2.86-3.00 (m, 2H), 3.05 (br. d, 1H), 3.66-3.82 (m, 3H), 3.80 (s, 3H), 3.89 (d, 1H), 3.94-4.06 (m, 2H), 4.20 (br. s, 1H), 4.45 (br. s, 1H), 6.92 (d, 1H), 7.06 (dd, 1H), 7.29 (d, 1H), 7.36 (d, 2H), 7.75-7.87 (m, 3H), 8.55 (dd, 1H), 9.28 (dd, 1H). LC-MS (Method 1): R_(t) = 0.82 min; m/z = 513 (M + H)⁺. 67

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.26 (d, 6H), 2.44-2.57 (m, 2H, obscured by DMSO signal), 2.84-3.00 (m, 2H), 3.06 (br. d, 1H), 3.34 (br. s, 1H, partially obscured by H₂O signal), 3.61-3.75 (m, 3H), 3.82 (s, 3H), 3.88 (d, 1H), 3.99 (s, 2H), 4.44 (br. s, 1H), 6.93 (d, 1H), 7.05 (dd, 1H), 7.36 (d, 2H), 7.80 (d, 2H), 8.55 (dd, 1H), 9.28 (dd, 1H). LC-MS (Method 1): R_(t) = 0.88 min; m/z = 547/549 (M + H)⁺. 68

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.26 (d, 6H), 2.41 (br. d, 1H), 2.46-2.58 (m, 1H, obscured by DMSO signal), 2.84-3.06 (m, 3H), 3.37 (br. s, 1H), 3.59 (br. d, 1H), 3.71 (br. t, 2H), 3.87 (d, 1H), 3.99 (s, 2H), 4.47 (br. s, 1H), 7.05 (dd, 1H), 7.24-7.33 (m, 2H), 7.37 (d, 2H), 7.42-7.54 (m, 2H), 7.79 (d, 2H), 8.55 (dd, 1H), 9.28 (dd, 1H). LC-MS (Method 1): R_(t) = 0.84 min; m/z = 500 (M + H)⁺. 69

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.19-1.31 (m, 6H), 1.52- 2.00 (m, 4H), 2.62 (br. dd, 0.75H), 2.70-2.85 (m, 1.5H), 2.89-3.03 (m, 2H), 3.21 (br. s, 0.75H), 3.43 (br. d, 1H), 3.70-3.86 (m, 3.75H), 4.22-4.35 (m, 2H), 4.38 (br. s, 0.25H), 6.85-6.96 (m, 1H), 7.05- 7.15 (m, 1H), 7.30-7.40 (m, 2H), 7.70-7.86 (m, 2.7H), 7.90 (d, 0.3H), 8.56 (dd, 1H), 8.94-9.04 (m, 1H). LC-MS (Method 2): R_(t) = 1.73 min; m/z = 531/533 (M + H)⁺. 70

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.81-0.95 (m, 2H), 0.96- 1.09 (m, 2H), 1.25 (d, 6H), 1.49- 1.63 (m, 1H), 1.66-2.00 (m, 3H), 2.44-2.57 (m, 0.7H, partially obscured by DMSO signal), 2.57- 2.65 (m, 0.3H), 2.73-3.02 (m, 4H), 3.36 (dd, 0.7H), 3.63-3.76 (m, 1H), 4.04 (br. d, 0.3H), 4.22-4.33 (m, 2H), 4.36 (br. s, 0.3H), 4.59 (br. s, 0.7H), 7.06-7.14 (m, 1H), 7.31-7.40 (m, 2H), 7.75-7.83 (m, 2H), 8.12-8.19 (m, 1H), 8.53-8.60 (m, 1H), 8.98-9.06 (m, 1H). LC-MS (Method 2): R_(t) = 1.52 min; m/z = 497 (M + H)⁺. 71

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.20-1.30 (m, 6H), 1.50- 2.01 (m, 4H), 2.69 (br. dd, 0.75H), 2.74 (br. s, 0.25H), 2.77-2.88 (m, 1.25H), 2.90-3.01 (m, 1.75H), 3.13 (br. d, 0.25H), 3.39-3.52 (m, 1.5H), 3.61 (d, 0.25H), 3.69-3.84 (m, 3.75H), 4.21-4.35 (m, 2H), 4.36-4.42 (m, 0.25H), 6.88-6.98 (m, 1H), 7.05-7.15 (m, 1H), 7.30- 7.40 (m, 2H), 7.70-7.83 (m, 3H), 8.52-8.60 (m, 1H), 8.96-9.06 (m, 1H). LC-MS (Method 2): R_(t) = 1.62 min; m/z = 515 (M + H)⁺. 72

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.20-1.31 (m, 6H), 1.51- 2.01 (m, 4H), 2.69 (br. dd, 0.75H), 2.74 (br. s, 0.25H), 2.77-2.87 (m, 1.25H), 2.89-3.02 (m, 1.75H), 3.14 (br. d, 0.25H), 3.39-3.52 (m, 1.5H), 3.61 (d, 0.25H), 3.69-3.83 (m, 3.75H), 4.21-4.35 (m, 2H), 4.36-4.42 (m, 0.25H), 6.88-6.98 (m, 1H), 7.05-7.15 (m, 1H), 7.30- 7.41 (m, 2H), 7.70-7.84 (m, 3H), 8.53-8.60 (m, 1H), 8.96-9.05 (m, 1H). LC-MS (Method 2): R_(t) = 1.63 min; m/z = 515 (M + H)⁺. 73

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.25 (d, 6H), 1.49-2.01 (m, 4H), 2.69-2.76 (m, 1H), 2.83- 3.02 (m, 3H), 3.39 (dd, 0.75H), 3.47 (br. d, 0.25H), 3.70-3.86 (m, 3.75H), 3.93-4.04 (m, 1H), 4.23- 4.35 (m, 2H), 4.39 (br. s, 0.25H), 6.84-6.95 (m, 1H), 7.05-7.14 (m, 1H), 7.17 (d, 0.75H), 7.26-7.40 (m, 2.25H), 7.73-7.85 (m, 3H), 8.52-8.60 (m, 1H), 8.97-9.06 (m, 1H). LC-MS (Method 2): R_(t) = 1.56 min; m/z = 497 (M + H)⁺. 74

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.25 (d, 6H), 1.49-2.01 (m, 4H), 2.69-2.76 (m, 1H), 2.82- 3.01 (m, 3H), 3.39 (dd, 0.75H), 3.47 (br. d, 0.25H), 3.70-3.85 (m, 3.75H), 3.93-4.02 (m, 1H), 4.23- 4.35 (m, 2H), 4.39 (br. s, 0.25H), 6.84-6.94 (m, 1H), 7.05-7.14 (m, 1H), 7.17 (d, 0.75H), 7.25-7.40 (m, 2.25H), 7.73-7.85 (m, 3H), 8.52-8.60 (m, 1H), 8.97-9.05 (m, 1H). LC-MS (Method 2): R_(t) = 1.55 min; m/z = 497 (M + H)⁺. 75

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.20-1.29 (m, 6H), 1.50- 2.01 (m, 4H), 2.71 (dd, 0.75H), 2.75 (br. s, 0.25H), 2.83-3.01 (m, 3H), 3.39 (dd, 0.75H), 3.47 (br. d, 0.25H), 3.73 (d, 0.75H), 3.93 (br. s, 1H), 4.23-4.34 (m, 2H), 4.39 (br. s, 0.25H), 7.05-7.13 (m, 1H), 7.14-7.22 (m, 1H), 7.31-7.41 (m, 2.25H), 7.45 (d, 0.75H), 7.48-7.71 (m, 1H), 7.75-7.82 (m, 2H), 7.97- 8.09 (m, 1H), 8.53-8.60 (m, 1H), 8.96-9.05 (m, 1H). LC-MS (Method 2): R_(t) = 1.68 min; m/z = 533 (M + H)⁺. 76

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.20-1.30 (m, 6H), 1.50- 2.01 (m, 4H), 2.71 (dd, 0.75H), 2.75 (br. s, 0.25H), 2.82-3.02 (m, 3H), 3.39 (dd, 0.75H), 3.47 (br. d, 0.25H), 3.73 (d, 0.75H), 3.93 (br. s, 1H), 4.23-4.35 (m, 2H), 4.38 (br. s, 0.25H), 7.05-7.13 (m, 1H), 7.14-7.23 (m, 1H), 7.31-7.41 (m, 2.25H), 7.45 (d, 0.75H), 7.49-7.71 (m, 1H), 7.75-7.83 (m, 2H), 7.97- 8.09 (m, 1H), 8.52-8.60 (m, 1H), 8.96-9.07 (m, 1H). LC-MS (Method 2): R_(t) = 1.69 min; m/z = 533 (M + H)⁺. 77

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.20-1.31 (m, 6H), 1.51- 2.00 (m, 4H), 2.03-2.12 (m, 3H), 2.63 (dd, 0.75H), 2.70-2.77 (m, 1H), 2.81 (d, 0.5H), 2.89-3.03 (m, 2H), 3.24 (br. s, 0.75H), 3.42 (br. d, 1H), 3.65-3.84 (m, 3.75H), 4.20-4.34 (m, 2H), 4.37-4.43 (m, 0.25H), 6.71-6.80 (m, 1H), 7.06- 7.14 (m, 1H), 7.29-7.41 (m, 2H), 7.54-7.65 (m, 1H), 7.72-7.83 (m, 2H), 8.52-8.60 (m, 1H), 8.95-9.05 (m, 1H). LC-MS (Method 6): R_(t) = 1.68 min; m/z = 511 (M + H)⁺. 78

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.19-1.31 (m, 6H), 1.51- 2.00 (m, 4H), 2.02-2.14 (m, 3H), 2.63 (dd, 0.75H), 2.69-2.78 (m, 1H), 2.81 (d, 0.5H), 2.89-3.03 (m, 2H), 3.24 (br. s, 0.75H), 3.42 (br. d, 1H), 3.65-3.84 (m, 3.75H), 4.20-4.35 (m, 2H), 4.37-4.43 (m, 0.25H), 6.70-6.80 (m, 1H), 7.06- 7.15 (m, 1H), 7.30-7.40 (m, 2H), 7.54-7.64 (m, 1H), 7.72-7.83 (m, 2H), 8.53-8.60 (m, 1H), 8.94-9.05 (m, 1H). LC-MS (Method 6): R_(t) = 1.68 min; m/z = 511 (M + H)⁺. 79

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.45-2.01 (m, 4H), 2.44- 2.57 (m, 0.5H), 2.59-2.86 (m, 2.5H), 2.89-3.07 (m, 1H), 3.36- 3.49 (m, 1H), 3.77 (br. d, 0.7H), 4.17-4.43 (m, 2.3H), 7.04-7.19 (m, 1H), 7.18-7.39 (m, 3H), 7.40-7.58 (m, 1H), 7.62-7.75 (m, 2H), 7.76- 7.91 (m, 2H), 8.54-8.63 (m, 1H), 8.96-9.07 (m, 1H). LC-MS (Method 2): R_(t) = 1.54 min; m/z = 520/522 (M + H)⁺. 80

81

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.52-1.99 (m, 4H), 2.67 (dd, 0.75H), 2.72 (br. s, 0.25H), 2.77-2.86 (m, 1.25H), 2.93 (br. s, 0.75H), 3.15 (br. d, 0.25H), 3.43 (dd, 0.75H), 3.48 (br. s, 0.75H), 3.57 (br. d, 0.25H), 3.70-3.83 (m, 3.75H), 4.22-4.34 (m, 2H), 4.36- 4.41 (m, 0.25H), 6.89-6.99 (m, 1H), 7.08-7.17 (m, 1H), 7.64-7.88 (m, 5H), 8.57-8.62 (m, 1H), 9.00- 9.08 (m, 1H). LC-MS (Method 2): R_(t) = 1.55 min; m/z = 551/553 (M + H)⁺. 82

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.60-1.83 (m, 4H), 2.39- 2.58 (m, 3H, partially obscured by DMSO signal), 2.75 (dd, 1H), 3.76 (s, 3H), 3.91 (br. s, 1H), 4.00-4.13 (m, 2H), 4.60 (br. s, 1H), 6.95 (dd, 1H), 7.14 (dd, 1H), 7.70 (d, 2H), 7.77 (t, 1H), 7.89 (d, 2H), 8.59 (dd, 1H), 9.06 (dd, 1H). LC-MS (Method 1): R_(t) = 0.93 min; m/z = 551/553 (M + H)⁺. 83

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.64-1.81 (m, 4H), 2.24 (br. d, 1H), 2.42 (br. d, 1H), 2.47- 2.60 (m, 1H, partially obscured by DMSO signal), 2.68 (br. d, 1H), 3.66 (br. s, 1H), 4.04 (s, 2H), 4.59 (br. s, 1H), 7.14 (dd, 1H), 7.24- 7.32 (m, 2H), 7.40-7.55 (m, 2H), 7.70 (d, 2H), 7.88 (d, 2H), 8.59 (dd, 1H), 9.04 (dd, 1H). LC-MS (Method 1): R_(t) = 0.93 min; m/z = 520/522 (M + H)⁺. 84

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.44-1.66 (m, 7H), 1.66- 1.80 (m, 5H), 2.26 (br. dd, 2H), 2.46-2.65 (m, 2H, partially obscured by DMSO signal), 2.80- 2.91 (m, 1H), 3.95-4.05 (m, 2H), 4.28 (br. s, 1H), 4.37-4.44 (m, 1H), 7.14 (dd, 1H), 7.70 (d, 2H), 7.90 (d, 2H), 8.59 (dd, 1H), 9.05 (dd, 1H). LC-MS (Method 1): R_(t) = 0.97 min; m/z = 494/496 (M + H)⁺.

Example 85 3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-N-(2,4-difluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

15.5 mg (0.10 mmol) of 2,4-difluorophenyl isocyanate were initially charged in a well of a 96-well multititre plate and cooled to 0° C. Separately, 46.3 mg of 2-(4-chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride were dissolved in 0.8 ml of 1,2-dichloroethane, 0.052 ml (0.3 mmol) of N,N-diisopropylethylamine was added, and the mixture was cooled to 8° C. The two solutions were combined in the multititer plate, 4 Å molecular sieve was added and first subjected to agitation at 0° C. for 1 h. Subsequently, the mixture was allowed to warm up to RT and agitated at RT overnight. Thereafter, the solvent was removed completely by means of a centrifugal dryer. The residue was dissolved in 0.6 ml of DMF and filtered, and the filtrate was separated into its components by preparative LC-MS by one of the following methods:

MS instrument: Waters, HPLC instrument: Waters; column: Phenomenex Luna 5μ C18(2) 100A, AXIA Tech., 50 mm×21.2 mm; mobile phase A: water, mobile phase B: acetonitrile, with mobile phase gradient; flow rate: 38.5 ml/min+1.5 ml/min 10% aq. formic acid; UV detection: DAD, 210-400 nm

or

MS instrument: Waters, HPLC instrument: Waters; column: Phenomenex Luna 5μ C18(2) 100A, AXIA Tech., 50 mm×21.2 mm; mobile phase A: water, mobile phase B: methanol, with mobile phase gradient; flow rate: 38.5 ml/min+1.5 ml/min 10% ammonia in water; UV detection: DAD, 210-400 nm.

In this way, 17.9 mg (35% of theory, 100% purity) of the title compound were obtained.

LC-MS (Method 7, ESIpos): R_(t)=1.14 min; m/z=509 (M+H)⁺.

In a parallel synthetic manner analogous to Example 85, the following compounds were prepared starting from 2-(4-chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride and the appropriate isocyanate, carbamoyl chloride or chloroformate:

Name/structure Example (yield, purity) LC-MS (Method 7)  86

R_(t) = 1.03 min; m/z = 439 [M + H]⁺  87

R_(t) = 0.99 min; m/z = 437 [M + H]⁺  88

R_(t) = 1.22 min; m/z = 571 [M + H]⁺  89

R_(t) = 1.19 min; m/z = 507 [M + H]⁺  90

R_(t) = 1.14 min; m/z = 523 [M + H]⁺  91

R_(t) = 1.15 min; m/z = 541 [M + H]⁺  92

R_(t) = 1.14 min; m/z = 501 [M + H]⁺  93

R_(t) = 1.13 min; m/z = 491 [M + H]⁺  94

R_(t) = 1.24 min; m/z = 541 [M + H]⁺  95

R_(t) = 1.17 min; m/z = 501 [M + H]⁺  96

R_(t) = 1.17 min; m/z = 507 [M + H]⁺  97

R_(t) = 1.29 min; m/z = 575 [M + H]⁺  98

R_(t) = 1.18 min; m/z = 515 [M + H]⁺  99

R_(t) = 1.17 min; m/z = 501 [M + H]⁺ 100

R_(t) = 1.14 min; m/z = 479 [M + H]⁺ 101

R_(t) = 1.09 min; m/z = 453 [M + H]⁺ 102

R_(t) = 1.07 min; m/z = 533 [M + H]⁺ 103

R_(t) = 1.27 min; m/z = 573 [M + H]⁺ 104

R_(t) = 1.16 min; m/z = 491 [M + H]⁺ 105

R_(t) = 1.10 min; m/z = 509 [M + H]⁺ 106

R_(t) = 1.25 min; m/z = 575 [M + H]⁺ 107

R_(t) = 1.16 min; m/z = 501 [M + H]⁺ 108

R_(t) = 1.22 min; m/z = 487 [M + H]⁺ 109

R_(t) = 1.16 min; m/z = 453 [M + H]⁺ 110

R_(t) = 1.03 min; m/z = 467 [M + H]⁺ 111

R_(t) = 1.23 min; m/z = 481 [M + H]⁺ 112

R_(t) = 1.30 min; m/z = 507 [M + H]⁺ 113

R_(t) = 1.10 min; m/z = 451 [M + H]⁺ 114

R_(t) = 1.25 min; m/z = 501 [M + H]⁺ 115

R_(t) = 1.14 min; m/z = 453 [M + H]⁺ 116

R_(t) = 1.16 min; m/z = 465 [M + H]⁺ 117

R_(t) = 1.30 min; m/z = 515 [M + H]⁺ 118

R_(t) = 1.33 min; m/z = 549 [M + H]⁺ 119

R_(t) = 1.05 min; m/z = 425 [M + H]⁺ 120

R_(t) = 1.26 min; m/z = 531 [M + H]⁺ 121

R_(t) = 1.23 min; m/z = 531 [M + H]⁺ 122

R_(t) = 1.13 min; m/z = 483 [M + H]⁺ 123

R_(t) = 1.10 min; m/z = 412 [M + H]⁺ 124

R_(t) = 1.15 min; m/z = 426 [M + H]⁺ 125

R_(t) = 1.26 min; m/z = 466 [M + H]⁺ 126

R_(t) = 1.21 min; m/z = 440 [M + H]⁺ 127

R_(t) = 1.35 min; m/z = 494 [M + H]⁺ 128

R_(t) = 1.30 min; m/z = 480 [M + H]⁺ 129

R_(t) = 1.29 min; m/z = 468 [M + H]⁺

Example 130 tert-Butyl 3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Under argon and at room temperature, 2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (700 mg, 2.64 mmol) was dissolved in 14 ml of THF, and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (672 mg, 3.17 mmol) was added. Sodium triacetoxyborohydride (839 mg, 3.96 mmol) was then added a little at a time, and the reaction solution was stirred at room temperature overnight. Then water was gradually and carefully added dropwise (caution: evolution of gas), and subsequently ethyl acetate was added. The resulting organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure on a rotary evaporator. The residue obtained was purified by column chromatography (Biotage Isolera, Biotage SNAP-KP-NH column; mobile phase: cyclohexane/ethyl acetate gradient). This gave 896 mg (1.94 mmol, 74% of theory) of the target compound.

LC-MS (Method 2): R_(t)=2.14 min; m/z=462 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.25 (d, 6H), 1.39 (s, 9H), 1.65 (br. s, 4H), 2.26 (br. d, 2H), 2.47-2.60 (m, 2H, partially obscured by DMSO signal), 2.95 (quin, 1H), 3.98 (s, 2H), 4.02 (br. s, 2H), 7.12 (dd, 1H), 7.37 (d, 2H), 7.83 (d, 2H), 8.56 (dd, 1H), 8.99 (dd, 1H).

Example 131 (5-Cyclopropyl-1,3-oxazol-4-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone

5-Cyclopropyl-1,3-oxazole-4-carboxylic acid (39 mg, 0.26 mmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (121 mg, 0.32 mmol) was added and the mixture was stirred at room temperature for 30 min. 3-(3,8-Diazabicyclo[3.2.1]oct-3-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (100 mg) and N,N-diisopropylethylamine (190 μl, 1.06 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 9). 65 mg (0.13 mmol, 61% of theory) of the title compound were obtained.

LC-MS (Method 2): R_(t)=1.81 min; MS (ESIpos): m/z=497 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.85-0.99 (m, 2H), 1.01-1.13 (m, 2H), 1.25 (d, 6H), 1.63-1.85 (m, 4H), 2.35-2.45 (m, 2H), 2.60-2.74 (m, 3H), 2.88-3.01 (m, 1H), 4.03 (s, 2H), 4.53-4.64 (m, 1H), 5.12 (br. s, 1H), 7.12 (dd, 1H), 7.37 (d, 2H), 7.85 (d, 2H), 8.17 (s, 1H), 8.57 (dd, 1H), 9.03 (dd, 1H).

Example 132 tert-Butyl 3-{[2-(4-cyclopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Under argon and at room temperature, 1090 mg (2.19 mmol) of tert-butyl 3-{[2-(4-bromophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate were initially charged in 15 ml of toluene and 3 ml of water in a 30 ml microwave vessel, and cyclopropylboronic acid (376 mg, 4.37 mmol), potassium phosphate (1625 mg, 7.65 mmol), palladium(II) acetate (49 mg, 0.22 mmol) and tricyclohexylphosphine (123 mg, 0.44 mmol) were then added. The microwave vessel was then closed and the mixture was heated to 120° C. and stirred at this temperature overnight. After cooling to room temperature, the reaction mixture was filtered through kieselguhr and the residue was washed a little at a time with ethyl acetate. More ethyl acetate and water were added to the filtrate obtained, and the phases were separated. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness. The residue was then stirred with diethyl ether. After filtration, the solid obtained was dried under high vacuum overnight. This gave 667 mg (1.36 mmol, 62% of theory) of the target compound.

LC-MS (Method 2): R_(t)=2.00 min; m/z=460 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.69-0.77 (m, 2H), 0.95-1.03 (m, 2H), 1.39 (s, 9H), 1.65 (br. s, 4H), 1.93-2.03 (m, 1H), 2.24 (br. d, 2H), 2.45-2.61 (m, 2H, partially obscured by DMSO signal), 3.97 (s, 2H), 4.02 (br. s, 2H), 7.11 (dd, 1H), 7.20 (d, 2H), 7.78 (d, 2H), 8.55 (dd, 1H), 8.99 (dd, 1H).

Analogously to Examples 13-29, the following compounds were prepared from the starting materials specified in each case:

Example Name/Structure/Starting materials Analytical data 133

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.70-0.77 (m, 2H), 0.95-1.02 (m, 2H), 1.65-1.79 (m, 4H), 1.93-2.02 (m, 1H), 2.24 (br. d, 1H), 2.41 (br. d, 1H), 2.56 (dd, 1H), 2.68 (dd, 1H), 3.66 (br. s, 1H), 4.03 (s, 2H), 4.59 (br. s, 1H), 7.12 (dd, 1H), 7.20 (d, 2H), 7.25-7.32 (br. s, 1H), 7.41-7.53 (m, 2H), 7.78 (d, 2H), 8.55 (dd, 1H), 9.00 (dd, 1H). LC-MS (Method 1): R_(t) = 0.87 min; m/z = 482 (M + H)⁺. 134

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.68-0.79 (m, 2H), 0.94-1.03 (m, 2H), 1.44-1.68 (m, 7H), 1.68-1.78 (m, 5H), 1.97 (tt, 1H), 2.18-2.30 (m, 2H), 2.53-2.65 (m, 2H), 2.80-2.90 (m, 1H), 3.94-4.03 (m, 2H), 4.28 (br. s, 1H), 4.41 (br. d, 1H), 7.11 (dd, 1H), 7.20 (d, 2H), 7.79 (d, 2H), 8.56 (dd, 1H), 9.01 (dd, 1H). LC-MS (Method 1): R_(t) = 0.90 min; m/z = 456 (M + H)⁺. 135

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.69-0.78 (m, 2H), 0.95-1.04 (m, 2H), 1.63-1.84 (m, 4H), 1.93-2.02 (m, 1H), 2.43 (br. t, 2H), 2.52-2.57 (m, 1H), 2.76 (dd, 1H), 3.75 (s, 3H), 3.91 (br. s, 1H), 3.99-4.09 (m, 2H), 4.61 (br. s, 1H), 6.95 (dd, 1H), 7.12 (dd, 1H), 7.20 (d, 2H), 7.73-7.81 (m, 3H), 8.56 (dd, 1H), 9.01 (dd, 1H). LC-MS (Method 1): R_(t) = 0.86 min; m/z = 513 (M + H)⁺. 136

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.68-0.78 (m, 2H), 0.94-1.03 (m, 2H), 1.62-1.83 (m, 4H), 1.93-2.02 (m, 1H), 2.33-2.44 (m, 2H), 2.45-2.56 (m, 1H, partially obscured by DMSO signal), 2.75 (dd, 1H), 3.62 (br. s, 1H), 3.78 (s, 3H), 3.99-4.10 (m, 2H), 4.60 (br. s, 1H), 6.92 (d, 1H), 7.12 (dd, 1H), 7.19 (d, 2H), 7.77 (d, 2H), 7.87 (d, 1H), 8.56 (dd, 1H), 9.00 (dd, 1H). LC-MS (Method 1): R_(t) = 0.90 min; m/z = 529/531 (M + H)⁺. 137

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.65-0.79 (m, 2H), 0.94-1.04 (m, 2H), 1.65-1.82 (m, 4H), 1.93-2.01 (m, 1H), 2.43 (br. d, 1H), 2.55-2.64 (m, 2H), 2.73 (dd, 1H), 3.77 (s, 3H), 3.98-4.09 (m, 2H), 4.63 (br. s, 1H), 4.69 (br. s, 1H), 6.92 (dd, 1H), 7.12 (dd, 1H), 7.20 (d, 2H), 7.35 (dd, 1H), 7.75-7.85 (m, 3H), 8.56 (dd, 1H), 9.02 (dd, 1H). LC-MS (Method 1): R_(t) = 0.87 min; m/z = 495 (M + H)⁺. 138

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.68-0.76 (m, 2H), 0.94-1.02 (m, 2H), 1.67-1.83 (m, 4H), 1.92-2.01 (m, 1H), 2.42 (br. d, 1H), 2.53-2.59 (m, 1H), 2.60-2.66 (m, 1H), 2.72 (dd, 1H), 4.04 (s, 2H), 4.57 (br. s, 1H), 4.64 (br. s, 1H), 7.11 (dd, 1H), 7.16-7.24 (m, 3H), 7.44 (s, 0.25H), 7.56-7.64 (m, 1.5H), 7.73 (s, 0.25H), 7.79 (d, 2H), 8.05 (t, 1H), 8.57 (dd, 1H), 9.03 (dd, 1H). LC-MS (Method 1): R_(t) = 0.91 min; m/z = 531 (M + H)⁺. 139

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.69-0.77 (m, 2H), 0.87-1.01 (m, 4H), 1.02-1.12 (m, 2H), 1.61-1.85 (m, 4H), 1.92-2.01 (m, 1H), 2.39 (br. t, 2H), 2.60-2.74 (m, 3H), 4.01 (s, 2H), 4.59 (br. d, 1H), 5.11 (br. s, 1H), 7.12 (dd, 1H), 7.20 (d, 2H), 7.80 (d, 2H), 8.17 (s, 1H), 8.56 (dd, 1H), 9.02 (dd, 1H). LC-MS (Method 1): R_(t) = 0.87 min; m/z = 495 (M + H)⁺.

B. ASSESSMENT OF PHARMACOLOGICAL EFFICACY

The pharmacological activity of the compounds of the invention can be demonstrated by in vitro and in vivo studies as known to the person skilled in the art. The application examples which follow describe the biological action of the compounds of the invention, without restricting the invention to these examples.

B-1. In Vitro Electrophysiological Analysis of the Human TASK-1 and TASK-3 Channels Via Two-Electrode Voltage Clamp Technique in Xenopus laevis Oocytes

Xenopus laevis oocytes were selected as described elsewhere by way of illustration [Decher et al., FEBS Lett. 492, 84-89 (2001)]. Subsequently, the oocytes were injected with 0.5-5 ng of a cRNA solution coding for TASK-1 or TASK-3. For the electrophysiological analysis of the channel proteins expressed in the oocytes, the two-electrode voltage clamp technique [Stüihmer, Methods Enzymol. 207, 319-339 (1992)] was used. The measurements were conducted as described [Decher et al., FEBS Lett. 492, 84-89 (2001)] at room temperature (21-22° C.) using a Turbo TEC 10CD amplifier (NPI), recorded at 2 kHz and filtered with 0.4 kHz. Substance administration was performed using a gravitation-driven perfusion system. Here, the oocyte is located in a measuring chamber and exposed to the solution stream of 10 ml/min. The level in the measuring chamber is monitored and regulated by sucking off the solution using a peristaltic pump.

Table 1 below shows the half-maximum inhibition, determined in this test, of human TASK-1 and TASK-3 channels (IC₅₀) by representative working examples of the invention:

TABLE 1 Example TASK-1 TASK-3 No. IC₅₀ [nM] IC₅₀ [nM] 19 239.4 ± 2.7  774.2 ± 67.1 21 19.2 ± 4.3 32.9 ± 6.0 26 31.2 ± 5.8 140.0 ± 34.6 27 17.9 ± 2.2 367.1 ± 67.6 28 20.5 ± 2.7  6.6 ± 0.8 29 21.0 ± 4.1 42.7 ± 8.4 41 44.4 ± 4.4  71.8 ± 15.5 51 21.7 ± 4.6 35.9 ± 8.2

From the data in Table 1 it is evident that both TASK-1 and TASK-3 are blocked. The results in Table 1 thus confirm the mechanism of action of the compounds according to the invention as dual TASK-1/3 inhibitors.

B-2. Inhibition of Recombinant TASK-1 and TASK-3 In Vitro

The investigations on the inhibition of the recombinant TASK-1 and TASK-3 channels were conducted using stably transfected CHO cells. The compounds according to the invention were tested in this case by application of 40 mM potassium chloride in the presence of a voltage-sensitive dye according to the method described in detail in the following references [Whiteaker et al., Validation of FLIPR membrane potential dye for high-throughput screening of potassium channel modulators, J. Biomol. Screen. 6 (5), 305-312 (2001); Molecular Devices FLIPR Application Note: Measuring membrane potential using the FLIPR® membrane potential assay kit on Fluorometric Imaging Plate Reader (FLIPR®) systems, http://www.moleculardevices.com/reagents-supplies/assay-kits/ion-channels/flipr-membrane-potential-assay-kits]. The activity of the test substances was determined as their ability to inhibit a depolarization induced in the recombinant cells by 40 mM potassium chloride. The concentration which can block half of this depolarization is referred to as IC₅₀.

Table 2 below lists the IC₅₀ values from this assay determined for individual working examples of the invention (some as mean values from multiple independent individual determinations):

TABLE 2 Example TASK-1 TASK-3 No. IC₅₀ [nM] IC₅₀ [nM] 1 1700 400 4 470 97 5 17000 1300 6 1400 41 7 8600 570 10 2200 130 11 2500 16 12 220 13 13 1500 33 14 7600 170 15 1100 19 16 670 12 17 1200 33 18 910 8.6 19 22000 59 20 160 38 21 140 4.2 22 340 5.2 23 1600 100 24 410 102 25 1100 71 26 1400 16 27 1200 10 28 290 3.2 29 280 1.8 30 3500 85 31 7100 140 32 370 29 33 190 130 34 76 29 35 6700 1500 36 310 80 37 1500 140 38 9600 320 39 1400 160 40 5700 210 41 1500 100 42 1000 340 43 1000 320 44 1000 190 45 1800 120 46 7600 140 47 2800 110 48 400 23 49 260 12 50 3300 430 51 250 8.7 52 1300 52 53 620 19 54 860 13 55 2900 170 56 5600 54 57 6400 57 58 1600 17 59 3000 39 60 670 430 61 3000 640 62 6900 70 63 1700 15 64 1100 8.4 65 3500 670 66 3700 20 67 1200 17 68 9400 87 69 2800 22 70 1900 20 71 14000 110 72 2100 29 73 9100 81 74 3400 61 75 3800 51 76 13000 56 77 720 4.9 78 3800 24 81 820 21 82 670 37 83 250 14 84 93 4.6 85 30000 1000 86 7700 430 89 30000 850 91 20000 410 92 15000 270 93 12000 260 94 30000 160 95 3000 41 97 31000 450 98 9000 160 99 30000 750 100 19000 630 101 19000 510 103 30000 690 104 19000 460 106 30000 89 107 30000 750 108 7000 90 109 24 1.5 110 13000 230 111 6300 290 112 15000 130 113 1100 62 114 6700 140 115 7400 330 116 2700 65 118 19000 220 119 5300 210 120 15000 230 121 12000 120 122 5000 120 123 14000 230 124 790 17 125 230 27 126 280 14 128 2000 110 130 1700 210 131 3500 410 132 1700 410 133 1600 180 134 770 97 135 420 34 136 320 41 137 1100 180 138 3200 290 139 4500 470

From the data in Table 2 it is evident that both TASK-1 and in particular TASK-3 are blocked. The results in Table 2 thus confirm the mechanism of action of the compounds according to the invention as dual TASK-1/3 inhibitors.

B-3. Animal Model of Obstructive Sleep Apnoea in the Pig

Using negative pressure, it is possible to induce collapse and thus obstruction of the upper respiratory tract in anaesthetized, spontaneously breathing pigs [Wirth et al., Sleep 36, 699-708 (2013)].

German Landrace pigs are used for the model. The pigs are anaesthetized and tracheotomized. One cannula each is inserted into the rostral and the caudal part of the trachea. Using a T connector, the rostral cannula is connected on the one hand to a device generating negative pressures and on the other hand to the caudal cannula. Using a T connector, the caudal cannula is connected to the rostral cannula and to a tube which allows spontaneous breathing circumventing the upper respiratory tract. By appropriate closing and opening of the tubes it is thus possible for the pig to change from normal nasal breathing to breathing via the caudal cannula during the time when the upper respiratory tract is isolated and connected to the device for generating negative pressures. The muscle activity of the Musculus genioglossus is recorded by electromyogram (EMG).

At certain points in time, the collapsibility of the upper respiratory tract is tested by having the pig breathe via the caudal cannula and applying negative pressures of −50, −100 and −150 cm water head (cm H₂O) to the upper respiratory tract. This causes the upper respiratory tract to collapse, which manifests itself in an interruption of the airflow and a pressure drop in the tube system. This test is conducted prior to the administration of the test substance and at certain intervals after the administration of the test substance. An appropriately effective test substance can prevent this collapse of the respiratory tract in the inspiratory phase.

After changeover from nasal breathing to breathing via the caudal cannula, it is not possible to measure any EMG activity of the Musculus genioglossus in the anaesthetized pig. As a further test, the negative pressure at which EMG activity restarts is then determined. This threshold value is, if a test substance is effective, shifted to more positive values. The test is likewise conducted prior to the administration of the test substance and at certain intervals after the administration of the test substance. Administration of the test substance can be intranasal, intravenous, subcutaneous, intraperitoneal or intragastral.

C. WORKING EXAMPLES OF PHARMACEUTICAL COMPOSITIONS

The compounds of the invention can be converted to pharmaceutical preparations as follows:

Tablet:

Composition:

100 mg of the compound of the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

Production:

The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (w/w) of the PVP in water. The granules are dried and then mixed with the magnesium stearate for 5 minutes. This mixture is compressed using a conventional tableting press (see above for format of the tablet). The guide value used for the pressing is a pressing force of 15 kN.

Suspension for Oral Administration:

Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.

10 ml of oral suspension correspond to a single dose of 100 mg of the compound of the invention.

Production:

The Rhodigel is suspended in ethanol; the compound of the invention is added to the suspension. The water is added while stirring. The mixture is stirred for about 6 h until the swelling of the Rhodigel is complete.

Solution for Oral Administration:

Composition:

500 mg of the compound of the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. 20 g of oral solution correspond to a single dose of 100 mg of the compound of the invention.

Production:

The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring operation is continued until dissolution of the compound of the invention is complete.

i.v. Solution:

The compound of the invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g. isotonic saline solution, glucose solution 5% and/or PEG 400 solution 30%). The solution is subjected to sterile filtration and dispensed into sterile and pyrogen-free injection vessels.

Solution for Nasal Administration:

The compound of the invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g. purified water, phosphate buffer, citrate buffer). The solution may contain further additives for isotonization, for preservation, for adjusting the pH, for improvement in the solubility and/or for stabilization. 

1-5. (canceled)
 6. A method for treatment or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders or neuroimmunological disorders, comprising administering to a human or animal in need thereof an effective amount of a compound of formula (I)

wherein the ring Q is a diazaheterobicyclic system of the formula

wherein * denotes the bond to the adjacent CHR² group and ** the bond to the carbonyl group; A is CH or N; R¹ is halogen, cyano, (C₁-C₄)-alkyl, cyclopropyl or cyclobutyl, wherein (C₁-C₄)-alkyl is optionally up to trisubstituted by fluorine, and cyclopropyl and cyclobutyl are optionally up to disubstituted by fluorine; R² is hydrogen or methyl; and R³ is (C₄-C₆)-cycloalkyl wherein a ring CH₂ group is optionally replaced by —O—; or R³ is a phenyl group of the formula (a), a pyridyl group of the formula (b) or (c) or an azole group of the formula (d), (e) or (f)

wherein *** marks the bond to the adjacent carbonyl group; and R⁴ is hydrogen, fluorine, chlorine, bromine or methyl; R⁵ is hydrogen, fluorine, chlorine, bromine, cyano, (C₁-C₃)-alkyl or (C₁-C₃)-alkoxy, wherein (C₁-C₃)-alkyl and (C₁-C₃)-alkoxy are optionally up to trisubstituted by fluorine; R⁶ is hydrogen, fluorine, chlorine, bromine or methyl; R⁷ is hydrogen, (C₁-C₃)-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono-(C₁-C₃)-alkylamino, di-(C₁-C₃)-alkylamino or (C₁-C₃)-alkylsulfanyl, wherein (C₁-C₃)-alkoxy may be up to trisubstituted by fluorine; R⁸ is hydrogen, fluorine, chlorine, bromine, (C₁-C₃)-alkyl or (C₁-C₃)-alkoxy, R^(9A) and R^(9B) are identical or different and are independently hydrogen, fluorine, chlorine, bromine, (C₁-C₃)-alkyl, cyclopropyl or (C₁-C₃)-alkoxy, wherein (C₁-C₃)-alkyl and (C₁-C₃)-alkoxy are optionally up to trisubstituted by fluorine; and Y is O or S; or R³ is an —OR¹⁰ or —NR¹¹R¹² group wherein R¹⁰ is (C₁-C₆)-alkyl, (C₄-C₆)-cycloalkyl or [(C₃-C₆)-cycloalkyl]methyl; R¹¹ is hydrogen or (C₁-C₃)-alkyl; and R¹² is (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, phenyl or benzyl, wherein (C₁-C₆)-alkyl is optionally up to trisubstituted by fluorine; and wherein phenyl and the phenyl group in benzyl are optionally up to trisubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy and (trifluoromethyl)sulfanyl; or R¹¹ and R¹² are attached to one another and, together with the nitrogen atom to which they are bonded, form a pyrrolidine, piperidine, morpholine or thiomorpholine ring, or a salt, a solvate, or a solvate of the salt thereof. 7-9. (canceled)
 10. A method for treatment or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders or neuroimmunological disorders, comprising administering to a human or animal in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I),

wherein the ring Q is a diazaheterobicyclic system of the formula

wherein * denotes the bond to the adjacent CHR² group and ** the bond to the carbonyl group; A is CH or N; R¹ is halogen, cyano, (C₁-C₄)-alkyl, cyclopropyl or cyclobutyl, wherein (C₁-C₄)-alkyl is optionally up to trisubstituted by fluorine, and cyclopropyl and cyclobutyl are optionally up to disubstituted by fluorine; R² is hydrogen or methyl; and R³ is (C₄-C₆)-cycloalkyl wherein a ring CH₂ group is optionally replaced by —O—; or R³ is a phenyl group of the formula (a), a pyridyl group of the formula (b) or (c) or an azole group of the formula (d), (e) or (f)

wherein *** marks the bond to the adjacent carbonyl group; and R⁴ is hydrogen, fluorine, chlorine, bromine or methyl; R⁵ is hydrogen, fluorine, chlorine, bromine, cyano, (C₁-C₃)-alkyl or (C₁-C₃)-alkoxy, wherein (C₁-C₃)-alkyl and (C₁-C₃)-alkoxy are optionally up to trisubstituted by fluorine; R⁶ is hydrogen, fluorine, chlorine, bromine or methyl; R⁷ is hydrogen, (C₁-C₃)-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono-(C₁-C₃)-alkylamino, di-(C₁-C₃)-alkylamino or (C₁-C₃)-alkylsulfanyl, wherein (C₁-C₃)-alkoxy may be up to trisubstituted by fluorine; R⁸ is hydrogen, fluorine, chlorine, bromine, (C₁-C₃)-alkyl or (C₁-C₃)-alkoxy, R^(9A) and R^(9B) are identical or different and are independently hydrogen, fluorine, chlorine, bromine, (C₁-C₃)-alkyl, cyclopropyl or (C₁-C₃)-alkoxy, wherein (C₁-C₃)-alkyl and (C₁-C₃)-alkoxy are optionally up to trisubstituted by fluorine; and Y is O or S; or R³ is an —OR¹⁰ or —NR¹¹R¹² group wherein R¹⁰ is (C₁-C₆)-alkyl, (C₄-C₆)-cycloalkyl or [(C₃-C₆)-cycloalkyl]methyl; R¹¹ is hydrogen or (C₁-C₃)-alkyl; and R¹² is (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, phenyl or benzyl, wherein (C₁-C₆)-alkyl is optionally up to trisubstituted by fluorine; and wherein phenyl and the phenyl group in benzyl are optionally up to trisubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy and (trifluoromethyl)sulfanyl; or R¹¹ and R¹² are attached to one another and, together with the nitrogen atom to which they are bonded, form a pyrrolidine, piperidine, morpholine or thiomorpholine ring, or a salt, a solvate, or a solvate of the salt thereof, in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.
 11. A method for treatment or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders or neuroimmunological disorders, comprising administering to a human or animal in need thereof an effective amount of at least one compound of formula (I)

wherein the ring Q is a diazaheterobicyclic system of the formula

wherein * denotes the bond to the adjacent CHR² group and ** the bond to the carbonyl group; A is CH or N; R¹ is halogen, cyano, (C₁-C₄)-alkyl, cyclopropyl or cyclobutyl, wherein (C₁-C₄)-alkyl is optionally up to trisubstituted by fluorine, and cyclopropyl and cyclobutyl are optionally up to disubstituted by fluorine; R² is hydrogen or methyl; and R³ is (C₄-C₆)-cycloalkyl wherein a ring CH₂ group is optionally replaced by —O—; or R³ is a phenyl group of the formula (a), a pyridyl group of the formula (b) or (c) or an azole group of the formula (d), (e) or (f)

wherein *** marks the bond to the adjacent carbonyl group; and R⁴ is hydrogen, fluorine, chlorine, bromine or methyl; R⁵ is hydrogen, fluorine, chlorine, bromine, cyano, (C₁-C₃)-alkyl or (C₁-C₃)-alkoxy, wherein (C₁-C₃)-alkyl and (C₁-C₃)-alkoxy are optionally up to trisubstituted by fluorine; R⁶ is hydrogen, fluorine, chlorine, bromine or methyl; R⁷ is hydrogen, (C₁-C₃)-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono-(C₁-C₃)-alkylamino, di-(C₁-C₃)-alkylamino or (C₁-C₃)-alkylsulfanyl, wherein (C₁-C₃)-alkoxy may be up to trisubstituted by fluorine; R⁸ is hydrogen, fluorine, chlorine, bromine, (C₁-C₃)-alkyl or (C₁-C₃)-alkoxy, R^(9A) and R^(9B) are identical or different and are independently hydrogen, fluorine, chlorine, bromine, (C₁-C₃)-alkyl, cyclopropyl or (C₁-C₃)-alkoxy, wherein (C₁-C₃)-alkyl and (C₁-C₃)-alkoxy are optionally up to trisubstituted by fluorine; and Y is O or S; or R³ is an —OR¹⁰ or —NR¹¹R¹² group wherein R¹⁰ is (C₁-C₆)-alkyl, (C₄-C₆)-cycloalkyl or [(C₃-C₆)-cycloalkyl]methyl; R¹¹ is hydrogen or (C₁-C₃)-alkyl; and R¹² is (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, phenyl or benzyl, wherein (C₁-C₆)-alkyl is optionally up to trisubstituted by fluorine; and wherein phenyl and the phenyl group in benzyl are optionally up to trisubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy and (trifluoromethyl)sulfanyl; or R¹¹ and R¹² are attached to one another and, together with the nitrogen atom to which they are bonded, form a pyrrolidine, piperidine, morpholine or thiomorpholine ring, or a salt, a solvate, or a solvate of the salt thereof.
 12. A pharmaceutical combination comprising a compound of formula (I),

wherein the ring Q is a diazaheterobicyclic system of the formula

wherein * denotes the bond to the adjacent CHR² group and ** the bond to the carbonyl group; A is CH or N; R¹ is halogen, cyano, (C₁-C₄)-alkyl, cyclopropyl or cyclobutyl, wherein (C₁-C₄)-alkyl is optionally up to trisubstituted by fluorine, and cyclopropyl and cyclobutyl are optionally up to disubstituted by fluorine; R² is hydrogen or methyl; and R³ is (C₄-C₆)-cycloalkyl wherein a ring CH₂ group is optionally replaced by —O—; or R³ is a phenyl group of the formula (a), a pyridyl group of the formula (b) or (c) or an azole group of the formula (d), (e) or (f)

wherein *** marks the bond to the adjacent carbonyl group; and R⁴ is hydrogen, fluorine, chlorine, bromine or methyl; R⁵ is hydrogen, fluorine, chlorine, bromine, cyano, (C₁-C₃)-alkyl or (C₁-C₃)-alkoxy, wherein (C₁-C₃)-alkyl and (C₁-C₃)-alkoxy are optionally up to trisubstituted by fluorine; R⁶ is hydrogen, fluorine, chlorine, bromine or methyl; R⁷ is hydrogen, (C₁-C₃)-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono-(C₁-C₃)-alkylamino, di-(C₁-C₃)-alkylamino or (C₁-C₃)-alkylsulfanyl, wherein (C₁-C₃)-alkoxy may be up to trisubstituted by fluorine; R⁸ is hydrogen, fluorine, chlorine, bromine, (C₁-C₃)-alkyl or (C₁-C₃)-alkoxy, R^(9A) and R^(9B) are identical or different and are independently hydrogen, fluorine, chlorine, bromine, (C₁-C₃)-alkyl, cyclopropyl or (C₁-C₃)-alkoxy, wherein (C₁-C₃)-alkyl and (C₁-C₃)-alkoxy are optionally up to trisubstituted by fluorine; and Y is O or S; or R³ is an —OR¹⁰ or —NR¹¹R¹² group wherein R¹⁰ is (C₁-C₆)-alkyl, (C₄-C₆)-cycloalkyl or [(C₃-C₆)-cycloalkyl]methyl; R¹¹ is hydrogen or (C₁-C₃)-alkyl; and R¹² is (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, phenyl or benzyl, wherein (C₁-C₆)-alkyl is optionally up to trisubstituted by fluorine; and wherein phenyl and the phenyl group in benzyl are optionally up to trisubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy and (trifluoromethyl)sulfanyl; or R¹¹ and R¹² are attached to one another and, together with the nitrogen atom to which they are bonded, form a pyrrolidine, piperidine, morpholine or thiomorpholine ring, or a salt, a solvate, or a solvate of the salt thereof, in combination with one or more further active compounds selected from the group consisting of respiratory stimulants, psychostimulating compounds, serotonin reuptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, sGC stimulators, mineralocorticoid receptor antagonists, antiinflammatory drugs, immunomodulators, immunosuppressives and cytotoxic drugs.
 13. A method for treatment or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders or neuroimmunological disorders, comprising administering to a human or animal in need thereof an effective amount of a pharmaceutical combination according to claim
 12. 14. The method according to claim 6, wherein the ring Q is a diazaheterobicyclic system of the formula

in which * denotes the bond to the adjacent CHR² group and ** the bond to the carbonyl group; A is CH; R¹ is chlorine, bromine, isopropyl or cyclopropyl; R² is hydrogen; and R³ is cyclopentyl or cyclohexyl; or R³ is a phenyl group of the formula (a), a pyridyl group of the formula (b) or an azole group of the formula (d), (e) or (f)

wherein *** marks the bond to the adjacent carbonyl group; and R⁴ is hydrogen, fluorine or chlorine; R⁵ is fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy; R⁶ is hydrogen, fluorine, chlorine, bromine or methyl; R⁷ is methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclobutyloxy or methylsulfanyl; R^(9A) and R^(9B) are identical or different and are independently hydrogen, methyl, trifluoromethyl, ethyl, isopropyl or cyclopropyl; and Y is O or S, or a salt, a solvate, or a solvate of the salt thereof.
 15. The method of claim 6, wherein the compound is tert-Butyl 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate of the formula


16. The method of claim 6, wherein the compound is (5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo [2.2.2]oct-2-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone of the formula


17. The method of claim 6, wherein the compound is (3-Fluoro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone of the formula


18. The method of claim 6, wherein the compound is ((3-Chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone of the formula


19. The method of claim 6, wherein the compound is (3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)[6-(methylamino)pyridin-2-yl]methanone of the formula


20. The method of claim 6, wherein the compound is (3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)(3-methoxyphenyl)methanone of the formula


21. The method of claim 6, wherein the compound is (5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)(cyclopentyl)methanone of the formula


22. The method of claim 6, wherein the method is a method for treatment of sleep-related respirator disorders.
 23. The method of claim 6, wherein the method is a method for treatment of obstructive sleep apnoeas.
 24. The method of claim 6, wherein the method is a method for treatment of central sleep apnoeas.
 25. The method of claim 10, wherein the method is a method for treatment of sleep-related respirator disorders.
 26. The method of claim 10, wherein the method is a method for treatment of obstructive sleep apnoeas.
 27. The method of claim 10, wherein the method is a method for treatment of central sleep apnoeas. 